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WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses. Geneva: World Health Organization; 2012.

Cover of WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses

WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses.

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This chapter presents and explains four of the more commonly used classification systems of pain. Several classification systems exist but no international classification system has been unanimously adopted. This chapter permits discrimination among the different terms used to categorize pain and the classification system to which each belongs. It also defines which classification system is relevant to the clinical management of pain and describes the most common causes of pain in HIV/AIDS, cancer and sickle cell disease.

1.1. Introduction to classification of pain

The International Association for the Study of Pain (IASP) defines pain as, “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (2). The definition emphasizes both the physical and emotional nature of pain. An additional note is pertinent to pain experienced by children: “The inability to communicate verbally does not negate the possibility that an individual is experiencing pain and is in need of appropriate pain-relieving treatment. Pain is always subjective ….” (3).

Pain is a multidimensional phenomenon with sensory, physiological, cognitive, affective, behavioural and spiritual components. Emotions (affective component), behavioural responses to pain (behavioural component), beliefs, attitudes, spiritual and cultural attitudes about pain and pain control (cognitive component) all alter the way that pain is experienced (sensory component) by modifying the transmission of noxious (unpleasant) stimuli to the brain (physiological component) (Figure 1.1).

Figure 1.1. Diagram showing the many dimensions of pain modifying the transmission of noxious stimuli to the brain.

Figure 1.1

Diagram showing the many dimensions of pain modifying the transmission of noxious stimuli to the brain.

The four most commonly used systems are (4, 5):

  • the pathophysiological mechanism of pain (nociceptive or neuropathic pain);
  • the duration of pain (chronic or acute, breakthrough pain);
  • the etiology (malignant or non-malignant);
  • the anatomic location of pain.

Some causes of persisting pain in children may result from (6):

  1. chronic diseases such as arthritis, sickle cell disease and rheumatologic disorders constitute important causes of musculoskeletal pain and chronic conditions such as inflammatory bowel disease can cause recurrent abdominal pain.
  2. trauma – physical, thermal, electrical and chemical injuries (e.g. burns) and lead to, for instance, phantom limb pain or lower back pain.
  3. life threatening diseases and their treatment such as simultaneous acute and chronic pain in cancer and HIV/AIDS.

Idiopathic pain has no identifiable etiology. Examples are most headaches and recurrent abdominal pain.1

Pain in specific disease conditions, such as cancer, HIV/AIDS and sickle cell disease, can be classified as mixed acute and/or chronic and may arise due to many of the causes discussed in Section 1.3.

1.2. Pain classification systems

1.2.1. Pathophysiological classification

There are two major types of pain, nociceptive and neuropathic. Clinical distinction between nociceptive and neuropathic pain is useful because the treatment approaches are different.

Nociceptive pain arises when tissue injury activates specific pain receptors called nociceptors, which are sensitive to noxious stimuli. Nociceptors can respond to heat, cold, vibration, stretch stimuli and chemical substances released from tissues in response to oxygen deprivation, tissue disruption or inflammation. This type of pain can be subdivided into somatic and visceral pain depending on the location of activated nociceptors.

  • Somatic pain is caused by the activation of nociceptors in either surface tissues (skin, mucosa of mouth, nose, urethra, anus, etc.) or deep tissues such as bone, joint, muscle or connective tissue. For example, cuts and sprains causing tissue disruption produce surface somatic pain while muscle cramps due to poor oxygen supply produce deep somatic pain.
  • Visceral pain is caused by the activation of nociceptors located in the viscera (the internal organs of the body that are enclosed within a cavity, such as thoracic and abdominal organs). It can occur due to infection, distension from fluid or gas, stretching or compression, usually from solid tumours.

Neuropathic pain is caused by structural damage and nerve cell dysfunction in the peripheral or central nervous system (CNS) (7). Any process that causes damage to the nerves, such as metabolic, traumatic, infectious, ischaemic, toxic or immune-mediated pathological conditions, can result in neuropathic pain. In addition, neuropathic pain can be caused by nerve compression or the abnormal processing of pain signals by the brain and spinal cord.

Neuropathic pain can be either peripheral (arising as a direct consequence of a lesion or disease affecting the peripheral nerve, the dorsal root ganglion or dorsal root) or central (arising as a direct consequence of a lesion or disease affecting the CNS). However, a clear distinction is not always possible.

Neuropathic pain has rarely been studied in infants, children and adolescents. Causes of peripheral neuropathic pain in children include nerve injury, nerve entrapment or external compression by any space-occupying lesion, such as a tumour or abscess; nerve damage caused by HIV infection or by the toxic effects of antiretroviral therapy (ART); benign tumours of the nerve, such as neurofibroma or scar neuroma after trauma or surgery; phantom limb pain; nerve infiltration by cancers; and nerve damage caused by cancer treatment (e.g. chemotherapy, radiation). Causes of central neuropathic pain include pain due to spinal cord injury. Furthermore, children can be affected by other neuropathic pain syndromes, such as congenital degenerative peripheral neuropathies and inflammatory neuropathies (e.g. Guillain-Barré syndrome) (8, 9). Many of the neuropathic conditions commonly seen in adults, such as diabetic neuropathy, post-herpetic neuralgia and trigeminal neuralgia, are rare in children.

Neuropathic pain is associated with many types of sensory dysfunction which are defined in Table 1.1.

Table 1.1. Common sensory features suggestive of neuropathic pain.

Table 1.1

Common sensory features suggestive of neuropathic pain.

Mixed pain. Neuropathic pain may coexist with nociceptive pain. In some disease conditions, patients may have mixed pain consisting of somatic, visceral and neuropathic pain all at the same time or each separately at different times. The different pathophysiological mechanisms described above can operate together to produce mixed pain. Examples include trauma that damages tissue and nerves, burns (that affect skin as well as nerve endings), and cancer that causes external nerve compression as well as damaging nerves by infiltration.

Clinical distinction between nociceptive and neuropathic pain is based on the anatomic origin of the stimulus, whether it is well-localized or diffuse, and the character of the pain (e.g. sharp, dull, burning) as described in Table 1.2.

Table 1.2. Differentiating features of nociceptive and neuropathic pain.

Table 1.2

Differentiating features of nociceptive and neuropathic pain.

In some types of painful conditions, the pathophysiological mechanisms of pain are not well understood and/or cannot be demonstrated. Such pain is often wrongly labelled as psychogenic. While psychological factors are known to influence the perception of pain, true psychogenic pain is very rare. Limitations in our current knowledge and diagnostic testing may also be the reasons for the inability to find any underlying cause and it is, therefore, recommended that the term idiopathic be used instead (10), thereby keeping open the possibility of diagnosing an organic process, which may reveal itself at a later stage or when more sensitive diagnostic tools become available.

If no physical pathology is found on clinical examination, laboratory tests and imaging studies, it is more effective to focus on rehabilitation and restoration of function than on repeated investigations.

All patients with pain should be treated with either pharmacological or non-pharmacological techniques irrespective of whether or not the underlying cause can be identified. Inability to establish an underlying cause should not be a reason to conclude that the pain is simulated.

1.2.2. Classification based on pain duration

A commonly used definition of acute pain is pain lasting less than 30 days, and a commonly used definition of chronic pain is pain lasting more then three months. However, these definitions are arbitrary and not essential for deciding on treatment strategies. Symptoms and causes of the two types of pain may overlap and pathophysiological factors can be independent of duration. Therefore, this division between acute and chronic pain based on duration may be problematic.

Acute pain is of sudden onset, is felt immediately following injury, is severe in intensity, but is usually short-lasting (4). It arises as a result of tissue injury stimulating nociceptors and generally disappears when the injury heals.

Chronic pain is continuous or recurrent pain that persists beyond the expected normal time of healing (3). Chronic pain may begin as acute pain and persist for long periods or may recur due to persistence of noxious stimuli or repeated exacerbation of an injury. Chronic pain may also arise and persist in the absence of identifiable pathophysiology or medical illness. Chronic pain can negatively affect all aspects of daily life, including physical activities, school attendance, sleep patterns, family interactions and social relationships and can lead to distress, anxiety, depression, insomnia, fatigue or mood changes, such as irritability and negative coping behaviour. As pain is an outcome of an interaction of many factors, the child as a whole must be considered when evaluating the clinical features of pain. Therefore, a holistic approach may be required to relieve pain.

Episodic or recurrent pain occurs intermittently over a long period of time and the child can be pain free in between each painful episode. Painful episodes can often fluctuate in intensity, quality and frequency over time and are consequently unpredictable. This type of pain may be indistinguishable from recurrent acute pain but might be associated with a more severe impact on the affected child's physical and psychosocial life. Examples of this type of pain include migraine, episodic sickle cell disease pain, recurrent abdominal pain. Persisting and recurrent pain can coexist, especially in conditions such as in sickle cell disease.

Breakthrough pain is characterized as a temporary increase in the severity of pain over and above the pre-existing baseline pain level, e.g. if a child is taking pain medicines and has good pain control with a stable analgesic regimen and suddenly develops acute exacerbation of pain. It is usually of sudden onset, severe, and of short duration. A number of episodes of breakthrough pain can occur each day. It is a well-known feature in cancer pain but it is also seen in non-malignant pain conditions (11, 12). Breakthrough pain can occur unexpectedly and independently of any stimulus, i.e. without a preceding incident or an obvious precipitating factor.

Incident pain or pain due to movement has an identifiable cause. The pain can be induced by simple movements, such as walking, or by physical movements that exacerbate pain, such as weight bearing, coughing or urination. Diagnostic or therapeutic procedures can also cause incident pain.

End of dose pain results when the blood level of the medicine falls below the minimum effective analgesic level towards the end of dosing interval.

The term “persisting pain” as used in these guidelines is intended to cover long-term pain related to medical illness, for example, pain associated with major infections (e.g. HIV), cancer, chronic neuropathic pain (e.g. following amputation), and episodic pain as in sickle cell crisis.

1.2.3. Etiological classification

Classification by etiology has little relevance to the mechanism and treatment of pain in children as categorization is commonly based on the underlying disease being malignant or non-malignant.

1.2.4. Anatomical classification

Pain is often classified by body location (e.g. head, back or neck) or the anatomic function of the affected tissue (e.g. myofascial, rheumatic, skeletal, neurological and vascular). However, location and function solely address the physical dimension and do not include the underlying mechanism (13). As such, although anatomical classifications can be useful for differential diagnoses, these classifications do not offer a framework for clinical management of pain.

1.3. Causes and classification of pain associated with specific diseases

1.3.1. Causes and types of pain in children with HIV/AIDS

Common types of pain experienced by infants with HIV include headache, oral cavity pain, abdominal pain, neuromuscular pain, chest pain, earache, odynophagia (pain while swallowing), myalgia and arthralgia (16, 17). In older children, the type of pain is often a function of the clinical stage of the infection. In early HIV, most pain occurs as a result of opportunistic conditions and is, therefore, somatic and transient in nature. During the later stages of the disease, somatic pain still occurs, but neuropathic pain, e.g. pain caused by peripheral neuropathy and myelopathy, is also seen.

The World Health Organization has provided paediatric clinical staging criteria for children infected with HIV. There are four clinical stages based on clinical symptoms, which may be used to guide medical decision-making (18):

  • Stage I: asymptomatic or persistent generalized lymphadenopathy;
  • Stage II: mucocutaneous manifestations, herpes zoster, and recurrent upper respiratory tract infections;
  • Stage III: unexplained persistent diarrhoea, unexplained persistent fever, oral candida, lymph node tuberculosis, pulmonary tuberculosis, and severe bacterial infection (e.g. pneumonia);
  • Stage IV: unexplained severe wasting or severe malnutrition, recurrent severe bacterial infections, and extrapulmonary tuberculosis.

Children with HIV/AIDS experience pain throughout the course of the disease. Disease-related pain can result from both infectious and non-infectious pathological conditions and can be acute or chronic. Pain associated with opportunistic infections (i.e. pneumonia, meningitis, gastroenteritis) should be considered, as should pain management for any procedures. In addition, the selection of therapeutic options must take into account the challenges associated with drug interactions. Below is a summary of types of pain seen in patients with HIV/AIDS characterized by location-associated symptoms and etiology (16, 19).

Causes of acute pain in HIV/AIDS

  • Oral cavity pain: aphthous ulcers, oral infections due to candida (white patches or red sores), herpes (cold sores), and cytomegalovirus may cause dysphagia, and pain which can be located on the tongue, gums, lips or roof of the mouth. There may be associated diarrhoea and vomiting. Oral cavity pain in turn leads to poor oral intake, increased weight loss, malnutrition, failure to thrive and progression to wasting syndrome (described below). In advanced cases of candidiasis, infection may extend into the oesophagus causing pain, especially when swallowing.
  • Abdominal pain can be caused by intestinal infections, urinary tract infection, pancreatitis, hepatitis and colitis. Diarrhoea and vomiting are commonly associated with abdominal pain. Cramping or episodic pain is often seen in settings where there is intestinal infection or bowel obstruction (e.g. secondary to inflammation). Children with HIV can also develop abdominal sepsis and present with an acute abdomen where pain is continuous, severe and exacerbated by movement.
  • Headache can be due to sinusitis, meningitis or encephalitis. Children with HIV can also experience noninfectious causes of headache such as tension headache and migraine. Infections of the central nervous system may give rise to fever, epileptic seizures as well as variability in consciousness along with pain.
  • Neurological and neuromuscular pain is common in the setting of static and progressive encephalopathy, especially when there is hypertonicity, spasticity and muscular spasms. Myopathy and herpes zoster are other important causes of neurological or neuromuscular pain.
  • Ear pain can occur due to infections of the middle ear (otitis media) or of the ear canal (otitis externa).
  • Skin pain caused by sores and rashes can occur due to infections (viral, bacterial or fungal). It can be both acute and chronic. Chickenpox and herpes simplex cause blisters that can hurt and itch. Skin pain may also be caused by acute cellulitis.
  • Chest pain: pneumonia and pulmonary tuberculosis accompanied by severe respiratory distress and coughing may cause both pain and distress.
  • Generalized pain: some children with HIV complain about generalized pain without any localizing site. Usually this type of pain is seen in very sick children.
  • Side-effects of antiretroviral therapy (ART) such as diarrhoea may induce painful complications such as diaper dermatitis. Medicine-specific side-effects include muscle pain (zidovudine), headache (efavirenz) and abdominal pain (stavudine).

Causes of persisting pain in HIV/AIDS

  • Neuropathic pain: peripheral neuropathy due to damage to the nerves by HIV and the adverse effect of ART described as discomfort, burning or numbness. In particular, nucleoside reverse transcriptase inhibitors – especially stavudine and didanosine – are associated with neuropathy (20). Herpes zoster infection may cause severe pain after the sores have healed, due to neuropathy (post-herpetic neuralgia).
  • Wasting syndrome can be associated with chronic diarrhoea (contributing to buttock ulceration and cramping), mouth and throat ulceration, fatigue, fever and weakness (enhancing any pain experience), depression, musculoskeletal pain, abdominal pain, and neuropathy secondary to nutritional deficiencies.

1.3.2. Causes and types of pain in children with cancer

In developed countries, most cancer pain in children is related to diagnostic and therapeutic procedures and treatment. Tumour-related pain often occurs at diagnosis, particularly when disease recurs and also occurs when the child's cancer is resistant to treatment. In developing countries, where large numbers of children with cancer present at an advanced stage and few have access to chemotherapy or radiotherapy, cancer pain is usually due to progression of the cancer itself (21).

The cancer mass can produce pain by tissue distension, compression or infiltration. Inflammation due to infection, necrosis or obstruction can also cause pain. The classification of cancer pain presents a unique challenge due to the complexity of the cancer pain in terms of variety of pathophysiological mechanisms and pain syndromes, and the need to provide information on prognosis and treatment outcomes. Disease-related pain in cancer can be acute or chronic (2123).

Causes of acute pain in children with cancer

Acute cancer pain can be caused by direct invasion of anatomical structures by the tumour, resulting in pain through pressure, distension, inflammation, obstruction and nervous tissue compression. Acute pain also occurs in relation to investigative or therapeutic procedures, such as bone-marrow aspiration and lumbar puncture. Incidental pain from unrelated causes or concomitant disease may also occur in children with cancer. Metastatic spinal cord compression may be a cause of acute back pain and metastatic brain tumour can cause severe headaches. Mucositis after chemotherapy or radiotherapy is also a frequent cause of pain in children with cancer.

Causes of persisting pain in children with cancer

Chronic pain can be either caused by the tumour growth itself or by various cancer-related diagnostic and therapeutic procedures, such as limb amputation or chemotherapy. The common childhood malignancies, such as leukaemia, lymphoma, bone sarcomas and neuroblastoma, can cause diffuse bone and joint pain. Leukaemia, brain tumours and lymphomas can cause headache. Neuropathic pain is caused by injury to the nervous system either as a result of a tumour compressing or infiltrating nerves or the spinal cord, or by damage caused by the treatment (chemotherapy, radiation). This type of pain is often severe and usually described as burning, tingling, sharp or shooting.

1.3.3. Causes and types of pain in children with sickle cell disease

Sickle cell disease (SCD) is a common genetic disorder characterized by the presence of abnormal haemoglobin (haemoglobin S) in the red blood cells. The term “sickle cell disease” is generally used to describe all conditions associated with the phenomenon of red blood cell sickling, whereas the term “sickle cell anaemia” is generally used to describe homozygosity for haemoglobin S (HbS). Apart from the latter, the disorder may result from different other genetic conditions, including compound heterozygosity for HbS and an abnormal haemoglobin (e.g. sickle cell haemoglobin) or HbS/beta-thalassaemia. All these conditions may have varying degrees of severity depending on the underlying genetic defect and interacting genetic factors. Individuals who are heterozygous for HbS (sickle cell trait) are usually asymptomatic. The presence of HbS causes red blood cells to become rigid and crescent shaped (i.e. sickled). When large numbers of sickled red blood cells collect, they hinder blood flow, which results in painful vaso-occlusive crises or episodes. The resultant ischaemia leads to tissue damage and cell necrosis, which cause nociceptive pain. Pain may originate from many sources (e.g. musculoskeletal and visceral) and children and adolescents experience both persisting and episodic pain (often defined as acute pain) (24, 25).

Episodic (acute) SCD pain occurs due to acute vaso-occlusive episodes (“sickle cell crises”). The arms, legs, abdomen, chest and back are the most common locations of pain episodes. Children describe pain associated with SCD as aching, tiring and uncomfortable. Children with SCD may experience pain as early as 6–12 months of age. On average painful episodes persist for four or five days, although protracted episodes may last up to three weeks. One of the more debilitating aspects of vaso-occlusive episodes is their unpredictable nature in terms of frequency, intensity, affected sites and duration of pain (25). It is thought that vaso-occlusive episodes are triggered by various environmental and psychological states, such as high altitudes, extreme temperatures, infection, dehydration, stress and fatigue (26). Painful episodes experienced by children with SCD often interfere with intellectual activities, such as attending school and completing homework; social activities, such as participating in activities with family members and peers; and the quality and quantity of sleep.

Persisting SCD pain is more common in adults than in children and more common in adolescents than in young children. Avascular necrosis due to poor blood oxygenation can cause chronic pain in limbs and joints. Poor circulation can lead to chronic leg ulcers. In addition, vertebral collapse can be the source of chronic back pain. As chronic pain increases in frequency and severity in a child with SCD, a cycle of inadequate coping skills, poor relationships, and worsening pain may sometimes develop (27).



Several types of headaches can affect children including migraine, tension, and cluster headaches.

Copyright © 2012, World Health Organization.

All rights reserved. Publications of the World Health Organization are available on the WHO web site ( or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: tni.ohw@sredrokoob). Requests for permission to reproduce or translate WHO publications - whether for sale or for noncommercial distribution - should be addressed to WHO Press through the WHO web site (

Bookshelf ID: NBK138356


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