Rossi , L. N. , Vajani , S. , Cortinovis , I. , Spreafi co , F. , and Menegazzo , L. ( 2008 ). Analysis of the International Classifi cation of Headache Disorders for diagnosis of mi graine and tension-type headache in children . Dev Med Child Neurol , 50 (4), 305 \200\223 310. Vannatta , K. , Getzoff , E. A. , Powers , S. W. , Noll , R. B. , Gerhardt , C. A. , and He rshey , A. D. ( 2008 ). Multiple perspectives on the psychological functioning of children with and without migraine . Headache , 48 (7), 994 \200\2231004. Ruangsuwan , S. , and Sriudomkajorn , S. ( 2007 ). 375 childhood primary headache: clinical features, the agreement between clinical diagnosis and diagnoses using the international c lassifi cation of headache disorders in Th ai children . J Med Assoc Th ai , 90 (7), 1309 \200\2231316. Varni , J. W. , Seid , M. , and Kurtin , P. S. ( 2001 ). PedsQL 4.0: reliability and validi ty of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy an d patient populations . Med Care , 39 (8), 800 \200\223812. Scagni , P. and Pagliero , R. ( 2008 ). Headache in an Italian pediatric emergency department . J Headache Pain , 9 (2), 83 \200\22387. SECTION 4 pain in specific populations and diseases 318 Wessman , M. , Terwindt , G. M. , Kaunisto , M. A. , Palotie , A. , and Ophoff , R. A. ( 20 07 ). Migraine: a complex genetic disorder . Lancet Neurol , 6 (6), 521 \200\223532. Vollono , C. , Ferraro , D. , Miliucci , R. , Vigevano , F. , and Valeriani , M. ( 2010 ). Th e abnormal recovery cycle of somatosensory evoked potential components in children with migraine can be reversed by topiramate . Cephalalgia , 30 (1), 17 \200\22326. Winner , P. and Hershey , A. D. ( 2007 ). Epidemiology and diagnosis of migraine in children . Curr Pain Headache Rep , 11 (5), 375 \200\223382. Walker , D. M. , and Teach , S. J. ( 2008 ). Emergency department treatment of primary head aches in children and adolescents . Curr Opin Pediatr , 20 (3), 248 \200\223254. Winner , P. , Pearlman , E. M. , Linder , S. L. , Jordan , D. M. , Fisher , A. C. , and Hul ihan , J. ( 2005 ). Topiramate for migraine prevention in children: a randomized, double-bl ind, placebo-controlled trial . Headache , 45 (10), 1304 \200\2231312. Wang , F. , Van Den Eeden , S. K. , Ackerson , L. M. , Salk , S. E. , Reince , R. H. , and Elin , R. J. ( 2003 ). Oral magnesium oxide prophylaxis of frequent migrainous headache in children: a randomized, double-blind, placebo- controlled trial . Headache , 43 (6), 601 \200\223610. Wojaczynska-Stanek , K. , Koprowski , R. , Wrobel , Z. , and Gola , M. ( 2008 ). Headache i n children \200\231s drawings . J Child Neurol , 23 (2), 184 \200\223191. Wang , S. J. , Fuh , J. L. , Juang , K. D. , and Lu , S. R. ( 2009 ). Migraine and suicidal ideation in adolescents aged 13 to 15 years . Neurology , 72 (13), 1146 \200\2231152. Wan g , W. , and Schoenen , J. ( 1998 ). Interictal potentiation of passive \200\230oddball \200\231 auditory event-related potentials in migraine . Cephalalgia , 18 (5), 261 \200 \223265. Yamane , L. E. , Montenegro , M. A. , and Guerreiro , M. M. ( 2004 ). Comorbidity headache and epilepsy in childhood . Neuropediatrics , 35 (2), 99 \200\223102. CHAPTER 32 Persisting pain in childhood medical illness Martha Mherekumombe and John J. Col lins Summary Persisting pain in the context of medical illness has been recognized recently as a global problem by the World Health Organization (WHO, 2012). Whilst the epidemiology of me dical illness varies throughout the world, the general principles of pain management are ap plicable to most medical illnesses in children and are eff ec- tive. Successful pain manage ment for most children is contingent on the availability of the WHO model list of essential medicines for children (WHO, 2011), although regrettably not all medicines are available i n every country in the world. \227\206 Th e availability of medicines on the WHO model list of essential medicines for children (WHO, 2011b ). \227\206 Using a two-step strategy for analgesic prescription: simple anal- gesics for mil d pain (step 1), opioids for moderate to severe pain (step 2). \227\206 Dosing of analgesics at regular intervals when pain is constant ( \200\230by the clock \200\231). It is also recommended that children with per- sisting pain have medicines available for breakthrough pain. As there is insuffi cient evidence to recommend a particu lar opioid or route of administration for breakthrough pain in children, there is a need to make an appropriate choice of treatment modality based on clinical judgment, medicine avai lability, pharmaco- logical considerations, and patient related factors. Introduction Pain is commonly experienced by children in the context of medi- cal illness. Th is may be due to acute or short-lived pain related to procedures for diagnostic, treatme nt, or surgical interventions. Persisting pain refers to any long-term pain and medical ill nesses refers to specifi c situations of ongoing tissue damage where there is a clear role for pharmacological treatment. Persisting pain in child- hood illness implies the duration of pain is lasting beyond what would be expected from an acute injury. Th is latter is curr ently the subject of a WHO initiative to improve management of persisting pain in children due to medical illness (WHO, 2012 ). Th is chapter discusses persisting pain in the context of non-malignant disease (HIV/AIDS, cystic fi brosis, neurofi bromatosis, neuromuscular di s- ease, cerebral palsy) and confi nes itself to a discussion of pharma- cological manageme nt. Th e reader is referred to other sections of this book for the issues and management of persisting pain due to other conditions and for non-pharmacological strategies for pain ma nagement. \227\206 Using the simplest route of administration and avoiding the intra- muscular route ( \200\230by the mouth \200\231). Th e choice of alternative routes of administration when the oral route is not possible should be based on clinical judgment, availability, feasibi lity, and patient preference. \227\206 Tailoring treatment to the individual child ( \200\230by the individual \200\231) . Among other WHO recommendations, paracetamol and ibuprofen are the medicines of choice in t he fi rst step (mild pain) and morphine is recommended as the fi rst-line strong opioid for the treatment of persisting moderate to severe pain in children with medical illnesses. Th e selection of alternative opioid analgesics to morphine should be guided by consideration s of safety, availability, cost, and suitability, including patient-related factors. Switch ing opioids and/or route of administration in children is recommended in the presence of in ad- equate analgesic eff ect with intolerable side eff ects. Routine rotation of opioids is not recommended (WHO, 2012 ). Opioids for the management of non-malignant pain in childhood Data on the management of sev ere pain using opioids in children with non-malignant disease is limited. One retrospective review studied opioid prescription for chronic severe non-malignant pain in a multidiscipl inary pediatric pain clinic. During a 12-month period, 104 patients were seen in the clinic , of which 49 received an opioid as part of their pain management; 11 received an opioid fo r more than 3 months, and fi ve of these were still receiving an opioid at the end of the s tudy period. Overall, there appeared to be better Th e pharmacological management of persisting pain in children with non-malignant illnesses Th e principles of pain management in the context of pediatric medical illness are broadly applicable to most disease processes. Th e correct use of analgesic medicines will relieve pain in most children with persisting pain due to medical illness and relies on the follow ing key concepts ( Box 32.1 ): SECTION 4 pain in specific populations and diseases 320 health system (WHO, 2012 ). It recommends the education of health professionals in the stan dardized management of persisting pain in children with medical illnesses and in the handli ng of the necessary medicines, including opioid analgesics. Further, health professionals s hould be allowed to handle opioids within their scope of practice or professional role base d on their general professional license without any additional licensing requirements. Indi vidual countries may con- sider, subject to their situation, allowing other professions to diagnose, prescribe, administer, and/or dispense opioids for reasons of fl exibil- ity, eff i ciency, increased coverage of services, and/or improved quality of care. Th e conditions under which such permission is granted would be based on the demonstration of competence, s uffi cient training, and personal accountability for professional performance (WHO, 2012 ). Box 32.1 WHO key concepts: the pain management of persisting pain in children with medical illness 1. Using a two-step strategy for analgesic prescription, simple analgesics for mild pain (s tep 1), opioids for moderate to severe pain (step 2). 2. Dosing at regular intervals when pain is constant ( \200\230by the clock \200\231). It i s also recommended that children with persisting pain have medicines available for breakthr ough pain. 3. Using the simplest route of administration ( \200\230by the mouth \200\231) and avoiding the intramuscular route. The choice of alternative routes of administration when the oral route is not possible should be based on clinical judgment, availability, feasibility, and patient preference. Human immunode \201 ciency virus and acquired immunode \201 ciency syndrome Human immunod efi ciency virus (HIV) causes immunosuppres- sion by infecting the immune system, in partic ular CD4 (cluster of diff erentiation 4, a glycoprotein expressed on the surface of T helpe r cells, monocytes, macrophages, and dendritic cells) lymphocytes. Immunosuppression from t he viraemia results in variable disease man- ifestations and disease progression (Luzuriaga and Sullivan, 1998 ). 4. Tailoring treatment to the individual child ( \200\230by the individual \200\231). pain control and improved function in these patients while receiv- ing opioid therapy in th e context of prescription in a multidiscipli- nary pain clinic with a multisystem approach to pain management. More data are needed to know if such therapy is safe and benefi cial on a longer-term basis (Slater et al., 2010 ). A growing number of children and young adults in the world are infected with HIV, with the majority of these in developing coun- tries. Approximately 3.4 million children under the a ge of 15 are liv- ing with HIV worldwide, and there were an estimated 390 000 newly infecte d children in 2010 (UNAIDS, 2011 ). Th e majority of these children live in sub-Saharan Afr ica where skilled clinicians, medica- tions, and technology limit the provision of optimal care (De Baets et al., 2007 ). In 2010 the estimated number of children with acquired immun odefi ciency disease (AIDS) who died in Sub-Saharan Africa was 230 000, 14 000 in South and South East Asia compared to less than 100 in North America, and Western and Central Europe (UNAIDS, 2011 ). Th e introduction of antiretroviral medication has dramatically changed t he course of HIV and children are surviving longer. In the absence of antiretroviral therap y (ART), HIV disease in children is more aggressive, with a signifi cant proportion of chil - dren presenting with severe disease. Th e rate of ART use in children under 15 years in d eveloping countries as estimated by WHO in 2010 was 23%, with between 3% to 29% in Africa ( WHO, 2011a ). Without ART pediatric HIV is usually more aggressive and most of the children die before the age of 5 years (WHO, 2011a ). Adjuvant analgesics for management of persisting pain in children with medical illness An a djuvant analgesic is a medicine that has a primary indication other than pain, but is analg esic in some painful conditions. Th is excludes medicines administered primarily to manage adverse eff ects associated with analgesics, such as laxatives and antiemetics. Th e WHO re cently reviewed the evidence for the use of adjuvant anal- gesic medicines in pain manageme nt for children (WHO, 2012 ). Th e use of corticosteroids as adjuvant medicines is not reco mmended for the treatment of persisting pain in children with medical illnesses, nor is the use of bisphosphonates for the treatment of bone pain in children due to the low quality o f evidence. Although frequently used for the management of neuropathic pain in children, it was not pos- sible to make evidence-based recommendations for or against the use of tricyc lic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), or anticonvuls ants as adjuvant medicines. In addi- tion, recommendations regarding the risks or benefi ts of ketamine or systemic local anesthetics as adjuvants to opioids for the treatment of neu ropathic pain in children, or for the use of benzodiazepines and/or baclofen as adjuvants i n the management of pain associated with muscle spasm and spasticity, could not be made bas ed on the current literature. Th e quality of current evidence, and risks and ben- efi ts o f diff erent treatments are summarized in the WHO document, and the need for further analge sic research in children with persist- ent pain and medical illness to establish the role o f these medicines in pediatric pain treatment is emphasized (WHO, 2012 ). Eff ective pain management is also hindered by limited availability of opioids in developin g countries. One study conducted in Africa showed approximately half of the children dying of AIDS received no analgesia (De Baets et al., 2007 ). It has been hypothesized that pain may be a unique manifestation of HIV and report of pain has been associated with a higher m ortality (Gaughan et al., 2002 ). Eff ective pain management could also be hindered by pote ntial drug interactions, and diffi culties in diff erentiating ongoing disease and treatmen t side eff ects (Straff ord et al., 1991 ). WHO health system recommendations for a global strategy to improve pain management in child ren In an eff ort to ensure the universal application of the general prin- ciples and clini cal recommendations, the WHO also makes health system recommendations acknowledging that la ck of access to the correct treatment for persisting pain is oft en related to issues in th e Prevalence of pain in children with HIV/AIDS Pain in children with HIV is highly prevalent (Gray et al., 2010 ) but is commonly unrecognized, inadequately treated, and not priori- ti zed (Norval et al., 2006 ). Earlier in the course of HIV, pain can be transient in nature ( Oleske, 2007 ), but as HIV progresses and the CD4 cell count decreases, pain can be severe (AIDSinfo, 2008 ). With CHAPTER 32 persisting pain in childhood medical illness 321 the fall in the CD4 cell count, children with progressive disease have more pain, which can become chronic and severe (De Baets et al., 2007 ; Gaughan et al., 2002 ; Lolekha et al., 2004 ). 2010 ; Yaster and Schechter, 1996 ; Yogev, 2011 ). Candida oesophagi- tis is a common probl em and risk factors for developing it include prior oral candidiasis, a low CD4 count, and antibiotic use. Pain can manifest as odynophagia (painful swallowing) or retrosternal pain. Infectious gastroenteritis from bacteria, parasites, viruses, or fungal agents can cause s mall and large bowel enteritis and severe abdomi- nal pain (Wilcox, 2010 ). Atypical infect ions such as Mycobacterium avium-intracellulare (MAI) can cause abdominal pain, usually rel ated to the accompanying lymphadenopathy (Wilcox, 2010 ). Patients with a CD4 count less th an 100/microlitre are more susceptible to CMV, fungi, Mycobacterium avium complex (MAC), an d unusual protozoa infections. CMV infection can cause pain through gastritis, a focal ulce r, gastric outlet obstruction, or gastric mass. It can also cause enteritis, small and larg e bowel perforation, colitis, appendicitis, hep- atitis, cholecystitis, cholangitis, and pa ncreatitis. Cryptosporidium causes gastritis, gastric outlet obstruction, small bowel enter itis, appendicitis, cholecystitis and hepatitis. Conversely, patients with a CD4 count grea ter than 400/microlitre are more likely to have com- mon bacterial infections or neoplasia (Wilcox, 2010 ). Th e prevalence of pain in children with HIV and AIDS is uncer- tain due to limited literat ure reports and few studies specifi cally related to in HIV-related pediatric pain. Reporte d prevalence of pain in children ranges from 20% (Gaughan et al., 2002 ) to 60% (Hirschfeld et al., 1996 ). Lolekha \200\231s cross-sectional study of a pae- diatric outpatient popul ation found 44% of children with HIV complained of pain and 6.6% of these children had pain lasting more than 3 months and occurring twice or more per week (Lolekha et al., 2004 ). A higher incidence of pain (67%) with associated sleep dis- turbance has been reported in yo unger children (67%) (Hirschfeld et al., 1996 ). Serchuck et al also reported a higher inci dence of pain in young children, and in girls (Serchuck et al., 2010 ). Gender dif- ference s are thought to be infl uenced by communication skills and cultural bias (Gaughan et al., 2002 ). Overall, the prevalence of pain in children with HIV/AIDS is comparable to that of pediatric can- cer pain (between 37% to 78%; Hirschfeld et al., 1996 ). Although pain is a frequent symptom, it unfortunately oft en con- tinues to be poorly treat ed (Yaster and Schechter, 1996 ). Some of the reasons include: lack of confi dence among he alth care profes- sionals in assessing and managing pain in children and miscon- ceptions s urrounding opioid use in children (AIDSinfo, 2008 ). Persisting pain can be also associated with increased mortality, a decreased quality of life (AIDSinfo, 2008 ), and increase in h ospital admissions (Josephs et al., 2010 ). Another rare cause of abdominal pain is gastrointestinal lym- phoma (Yaster and Schechter, 1996 ) which may present as a mass causing obstruction, hepatic, splenic, or mesenteric inf i ltration (New York State Department of Health AIDS Institute, 2001; Wilcox 2010 ; Yogev, 2011 ). Nucleoside reverse transcriptase inhibitors (NRTIs) used in therapy can cause mitochondrial toxicity, hepatic steatosis, and abdominal pain, and there are limited reported cases in c hildren (McComsey and Leonard, 2004 ). Complications from ART (dida- nosine, or lamivudine) include pancreatitis with or without abdom- inal pain and hepatitis. Causes of pain in HIV/AIDS HIV/AIDS pain is multifactorial and can arise from: complication s of the disease (e.g. infections, infl ammation, neoplasms), adverse drug reactions, and c ompromised immune status. Pain may be exac- erbated by: psychological factors such as stres s, clinical depression, anxiety, and fear; greater socioeconomic stresses (Serchuck et al., 2010 ); and also by poor nutritional status (AIDSinfo, 2008 ; Berg et al., 2009 ; De Baets et al., 2007 ; Gaughan et al., 2002 ; Hirschfeld et al., 1996 ; Serchuck et al., 2010 ). Neuropathic pain in children with HIV/AIDS Th e nervous system is major target for HIV infe ction, which can aff ect both the central and the peripheral nervous systems. Th e nervous system can be aff ected in multiple ways: as a direct consequence of opportunistic infectio ns or malignancies occurring because of immu- nosuppression, from treatment-related neuroto xic eff ects, or sys- temic complications of HIV on brain function (Dobalian et al., 2004 ) . Possible HIV-related immunological mechanisms include antigen \200\223 antibody immune co mplex deposition in blood vessels, causing a vas- culitis in small, medium, and large vesse ls. Evidence supporting this includes the demonstration of HIV p24 antigen in endoneurial b lood vessels, HIV replication in nerve biopsies, and the presence of HIV in cultures of ner ve tissue (Brinley et al., 2001 ; Epstein et al., 1986 ). Disease-related pain can aff ect many organs, predominately the gastrointestinal, neurologi cal, pulmonary, and dermatological sys- tems (AIDSinfo, 2008 ; Straff ord et al., 1991 ). T h e most frequent cause of pain in children with HIV was gastrointestinal or limb pain (Hir schfeld et al., 1996 ). Other causes of somatic pain include painful disorders of the skin, connective tissue, muscle, bone, and visceral pain. Somatic pain tends to be well localize d, sharp, and acute whilst visceral pain is less localized and is oft en described as deep, dull, aching, gnawing or spasmodic pain (Amery et al., 2009 ). More generalized bodily pai n, headache, chest or neuropathic pain can also occur. A survey of ambulatory adult patient s with HIV in the US reported somatic pain in 45% of cases, visceral pain in 15%, neuropath ic pain in 19%, and in 4% of cases the causes of pain were unknown (Hewitt et al., 1997 ). Peripheral neuropathy Peripheral neuropathy is reported to occur in about 13% to 34% of chi ldren with HIV/AIDS (AIDSinfo, 2011 ; Araujo et al., 2000 ). Approximately 34% of children in early or later stages of HIV report symptoms and signs of peripheral neuropathy in the a bsence of potential neurotoxic ARV drugs (Serchuck et al., 2010 ; Van Dyke et al., 2008 ). However, there is a higher prevalence of peripheral neu- ropathy in children with encephalo pathy and symptomatic AIDS. Peripheral neuropathy in children is oft en not as severe, freq uent, or debilitating as that which occurs in adults (Araujo et al., 2000 ; Floeter et al., 1997 ). It is unclear whether the peripheral nervous system of children is more resilient to neuropathic insults associated with HIV infection or whether few reports refl ects an un der diagnosis of peripheral neuropathy in this patient group (Floeter et al., 1997 ). Gastrointestinal pain in children with HIV/AIDS Immunosuppression causing infection and con sequent pain can manifest in any part of the gastrointestinal system. Pain can result from oropharyngeal candidiasis, dental caries, gingivitis, aphthous ulcers, herpetic stomatitis and oesophagitis from candida, cytome- galovirus (CMV), herpes simplex virus (HSV), or myco bacterium (New York State Department of Health AIDS Institute, 2001; Wilcox, SECTION 4 pain in specific populations and diseases 322 Th e incidence of ART-associated neuropathy is 0.1% with use of stavudine, lamivudine, and nevirapine (AIDSinfo, 2011 ). Th e toxic- ity of non-reverse transcriptase inhibitor (NRTI) therapy is thought to result from mitochondrial toxicity resulting in peripheral neu- ropa thy, myopathy, lactic acidosis, hepatitis, hepatitis steatosis, cardiomyopathy and lipoatro phy/lipodystrophy. Not all children on combination ART, which includes an NRTI, develop per ipheral neuropathy (Araujo et al., 2000 ; Floeter et al., 1997 ). HIV-positive adult Caucas ian patients who have the mitochondrial haplo-group T have an increased risk of peripheral neuropathy (Hulgan et al., 2005 ; Van Dyke et al., 2008 ). Van Dyke and colleagues postulat ed that the mitochondrial DNA polymorphism that predisposes to NRTI-induced mitochondrial t oxicity is uncommon in children from an African American or Hispanic background (Van Dyke e t al., 2008 ). Modest rates of toxicity have also been observed in younger children althoug h not fully defi ned in pediatrics. Bisphosphonates have been used to treat this type of pain and should be considered despite limited use in ARV treated HIV-infected chil- dren. Another bone problem seen in children i s avascular necrosis or osteonecrosis presenting as hip pain (McComsey and Leonard, 2004 ). When bone pain occurs, the recommended fi rst-line therapy is generally a non-steroidal an ti-infl ammatory (NSAID) provided there are no contraindications to its use. Idiopathic polymyositis, myositis secondary to zidovudine (AZT) toxicity, and infectious py omyositis can cause muscular pain in HIV-infected children (Lane, 1998 ). Muscular pain fro m AZT may occur as a result of an idiosyncratic reaction causing muscle weak- ness and elev ation of muscle enzymes and can occur at all CD4 lev- els. Discontinuing or reducing AZT do se may reduce pain severity. Procedural pain and its impact in children with HIV/AIDS Children with HIV/AIDS may experie nce many painful procedures such as venepuncture, bone marrow aspirate, lumbar puncture, or nasogastric tube insertion. An early report documented a total of 193 painful procedures i n 22 children with AIDS (Straff ord et al., 1991 ). Th e heightened pain experience from re peated painful procedures may contribute to a higher pain report in younger children (Serch uck et al., 2010 ). Procedural pain management is essential to minimize the experience of p ain. Comprehensive guidelines are available which out- line pharmacological and non-pharmac ological approaches to com- mon procedures, including preprocedure preparation (Amery et al ., 2009 ; Schiff et al., 2001 ). (Additional information related to proce- dural pain manag ement is included in Chapter 18 (Palmer and Babl), Chapter 19 (Taddio), and Chapter 47 (Zem psky) in this volume.) Neuropathic pain predominately occurs in the distal lower limbs, particularly in the feet ( Araujo et al., 2000 ; Floeter et al., 1997 ). Th e pain is usually described as aching, bur ning, or painful numb- ness (AIDSinfo, 2011 ). Some experience hyperalgesia and allody- nia . Paradoxical hyperalgesia in association with escalating drug requirements has been report ed in children undergoing prolonged intensive and invasive care (AIDSinfo, 2011 ; Gray et a l., 2010 ). However, neuropathic pain can be fl uctuating in nature and may not interfere w ith daily activities. Chronic sensory symptoms pre- dominate, with bilateral and distal pai n and paraesthesia, similar to reports in adults (Araujo et al., 2000 ). Headache in children with HIV/AIDS Headache in HIV/AIDS can result from meningitis or menin goen- cephalitis opportunistic infections. Bacterial meningitis commonly presents with head ache (Gumbo et al., 2002 ). Other causes of head- ache include sinusitis, central nervous s ystem (CNS) lymphoma, viral encephalopathy, and rarely toxoplasmosis, and Cryptococcus neof ormans . Opportunistic infections from toxoplasmosis, and CMV are uncommon in children, as infection is usually from reac- tivation of a previously acquired infection. Special considerations for pain management in children with HIV/AIDS Management of HIV/AIDS -related pain may be complex. It is important to recognize pain, assess its severity, and d evelop treat- ment goals for managing pain in the context to the HIV symptoma- tology (New York State Department of Health AIDS Institute, 2001). Th e availability of medications als o has an impact on pain manage- ment. Poorly controlled HIV-related pain can aff ect a chil d \200\231s quality of life, interfering with activity and sleep (AIDSinfo, 2008 ). Although meningoencephalitis from Cryptococcus neoformans is rare in children living with A IDS compared to adult patients, there may be an increasing number of African children aff e cted (Gumbo et al., 2002 ). Th e other causes of headache include complications of ART such as zidovudine, causing an adverse reaction. Tension headaches and migraine are reported in adults but the frequency in children is unknown. Dihydroergotamine or ergotamine should no t be co-administered with protease inhibitors as this may cause ergot toxicity resulting in nausea, vomiting, and sustained vasoconstric- tion with local tissue hypoxia and ischemic injury. Children with HIV/AIDS can develop spasticity and rigidity due to CNS com- plicatio ns of infection causing considerable pain and immobility. Management of this pain involves a multidisciplinary approach help improve comfort and mobility of these patients (AIDSinfo, 2011 ). Treating pain in HIV/AIDS requires a multimodal approach. Diagnosing and treating the cause of pain is vital, particularly as lowering the viral load could contribute to an improved response to analgesics (AIDSinfo, 2008 ). Th e goals of treatment should also be focused on reducing the incidence and severity of treatment-related pain. Age-appropriate pain severi ty measurement scales should be used and implementation of the principles of pain managemen t as recently outlined by the WHO (WHO, 2012 ). Generally, mild pain is treated with simple analgesia such as para- cetamol and NSAIDs. How ever, NSAIDs should be used with cau- tion as they may exacerbate bone marrow suppression a nd worsen gastrointestinal symptoms in patients with HIV and have potential drug \200\223dr ug interactions with ARV (Gray et al., 2010 ). Musculoskeletal pain in children with HIV/AIDS Bone pain in children with HIV/AIDS can be d ue to multiple causes that include: osteopenia as a result of bone loss and altered bone me tabolism, cancer, and infections such as osteomyelitis or septic arthritis. Decreased bone mineral density is seen in children with HIV/AIDS (Fortuny et al., 2008 ), the pathogenesis of which is likely to be multifactorial including mineral and vitamin defi ciency. Protease inhibitors (PIs), NNRTI or NRTIs can have signifi - cant drug interactions with an algesics, including buprenorphine, codeine, dextropropoxyphene, diamorphine, fentanyl, mefe namic acid, pethidine, tramadol, and ketamine. Th e simultanous use of these medications ma y result in increased plasma drug concentra- tions, toxicity, or relative overdose of the p ain medications. Th ese interactions can be managed by altering the drug dosage or timing CHAPTER 32 persisting pain in childhood medical illness 323 of administration as well as therapeutic drug monitoring (TDM). For example, cautious use o f methadone is employed in patients on PIs and NNRTIs as these drugs can induce the metabol ism of meth- adone and lead to withdrawal symptoms. Dosing of methadone therefore need to b e increased whilst on these ARV. Conversely, methadone toxicity has been reported with the discontinuation of PIs or NNRTIs (AIDSinfo, 2008 ). Case example: human immunode \201 ciency virus and acquired immunode \201 ciency syndrome Moses is a 4-year-old with AIDS whose parents had recently died from the same diagnosis. He was admitted to hospital in Africa with vomiting, diarrhea, and pain. He was noted to have mouth ulcers, severe oral thrush, a cough, and noted to be underweight with signs of malnu trition, and clinically dehydrated. He was distressed and in severe pain, but unable to loc alize the pain. His initial management included oral morphine (which he vomited), intraveno us fl uids, antibiotics, and topical oral antifungals. His pain worsened and his hospital h ad access to an intrave- nous morphine preparation, as recommended by the WHO model list of essential medicines for children (WHO, 2011b ). A regular schedule of subcutaneous morphin e was started for the management of constant severe pain. His pain severity decreased and e ventually his pain was well managed with a regu- lar schedule of oral morphine once his vom iting stopped. Further investigations showed he also had tuberculosis (TB) and anti-TB ther apy was commenced. In addition to this, the hepatic isoenzyme changes induced by these pain medications can al ter PI or NNRTI pharmacokinetics (AIDSinfo, 2008 ). Conservative dosing is therefore recomm ended, with titration against individual response. Dosing guidelines exist for adults for a ntiretroviral drug interactions (Ammann, 2009 ) and interactions can be managed by altering the drug dosage or timing of adminis- tration as well as TDM. However, there is no univers al rule for ARV dose calculation in children that can be considered accurate under all circ umstances. Body weight is the most accessible and widely used metric, but is also the mostl y likely to result in inaccurate dosing. Body surface area (BSA) is recommended as it more closely meets the effi cacy and safety requirements for infants and children (Norval et al. , 2006 ). However, as BSA does not take height into account, dos- ing based on the BSA shou ld be used with caution in children with malnutrition. Careful monitoring of organ function through appro- priate laboratory diagnostic tests, a patient \200\231s clinical status, we ight gain, increased growth and development, decreased opportunistic infections, increased CD4 counts, and decreased viral loads can be used to confi rm effi cacy of the ART (Norval et al., 2006 ). Cystic \201 brosis Cystic fi brosis (CF) is an inherited multisystem disorder, and the pr imary defect relates to dysfunction of the cystic fi brosis trans- membrane conductance reg ulator protein (CFTR). CF is character- ized by obstruction and infection of airways and by maldigestion and its consequences. As a result, CF is the major cause of severe chronic lu ng disease in children, and of most cases of exocrine pan- creatic insuffi ciency in early life (Egan, 2011 ). Due to the wide array of presenting symptoms and complications, CF ente rs the diff eren- tial diagnosis of many pediatric conditions (Egan, 2011 ). CF is the most common life-limiting recessive genetic trait among white peo- ple, with a prevalence of ap proximately 1/3500 live births in north- ern Europe, North America, and Australia and New Z ealand. Th e prognosis for children living with CF has improved dramatically over the last few decades. Th is is due to several factors including improved nutrition and improved trea tment of respiratory infec- tions. Notwithstanding this improvement in prognosis, this illn ess is still associated with signifi cant morbidity, but there has been little evaluation o f the extent and impact of pain on children with CF. Special considerations for pharmacotherapy in HIV/AIDS Excessive activation of the N-methyl -D-aspartate (NMDA) recep- tor occurs in the presence of gp120, a protein found on the oute r envelope of HIV (AIDSinfo, 2008 ). It is thought that this may con- tribute to increased pain severity potentially requiring escalating opioid and sedative requirements. Both dextr omethorphan and ketamine block the NMDA receptor, but their use can be limited by an unfavo rable side eff ect profi le. Ketamine has anecdotally been associated with severe cardiac r hythm disturbance, electrolyte abnormalities, and even cardiac arrest in children with adva nced HIV and AIDS (AIDSinfo, 2008 ). Adult literature suggests that methadone administratio n may be associated with lower CD4 cell count and CD4/CD8 cell ratios and in vitro studies also suggest an increase in HIV replication in human blood monocyte-derived macrophages exp osed to methadone (AIDSinfo, 2008 ). Pain in cystic \201 brosis Recognition that pain is a common symptom in children with CF was fi rst established in the 1990s. A retrospective chart review at a tertiary care hospit al was conducted summarizing the end-of-life care of US patients more than 5 years of age a nd dying from CF (Robinson et al., 1997 ). Twenty-fi ve per cent of these patients had been receiving opioids for the treatment of chronic headache and/ or chest pain for more than t heir last 3 months of life. When opio- ids were used for the treatment of breathlessness an d/or chest pain, the proportion increased to 86%. When pain was present, it was described a s \200\230serious \200\231 pain with chest, head, extremity, abdomen, and back being the m ore common locations. Myopathic pain is managed by fi rstly addressing the underlying cause, decreasing infl amma tion, and maximizing ART. Neuropathic pain and peripheral neuropathy due to medication is m anaged by stopping medications that produce neuropathy, and using analgesics as per the WHO recommendations (WHO, 2012 ). Neuropathic pain may also be managed with -aminobutyric a cid agonists (GABA) such as baclofen, ART, NMDA receptor blockade, and anticonvulsants (AID Sinfo, 2008 ). Abdominal pain from infl ammatory processes such as pancreatitis, infection, gall bladder and biliary tract disease, mal- absorption syndromes, tumors, and medication side eff ects can all cause persisting pain in children with HIV/AIDS. Mouth pain from apht hous ulcers and dysphagia are managed by using mouth washes, a soft brush, having soft food , and appropriate analgesia. Candidiasis should be treated with antifungals such as miconaz ole, fl uconazole, and topical anesthetics for local pain relief. Aphthous ulcers have also been managed with prednisolone and dexamethasone mouth washes. Th e incidence of chronic pain in children with CF increases sharply in the last 6 months o f life (Ravilly et al., 1996 ). Headaches (55% of patients) and chest pain (65%) were frequ ently reported, although back pain (19%), abdominal pain (19%), and limb pain SECTION 4 pain in specific populations and diseases 324 (16%) were also common. In patients with headache, the main aeti- ologies were hypercarbia or hypoxia, migraine, and sinusitis. Th e majority of chest pain was musculoskeletal, with pleuritis, pneu- mothorax, and rib fracture also reported. and neurofi bromatosis 2 (NF2; Sahin, 2011 ). NF1 is more com- mon and has a better prognos is with a lower incidence of CNS tumors than NF2, but may still be associated with signifi cant morbidity. A recent comparative study of children and adults with CF exam- ined the prevalence of pain in CF and the consequences to activities of daily living (Sermet-Gaudelus et al., 2009 ). Th e study included 73 children (1 \200\22318 years) and 110 adults (18 \200\22352 years); 59% of the children and 89% of the adults reported at least one episode of pain during the previous month. Pain was signifi cantly more intense and lasted signifi cantly longer among adults, but incidence did not dif- fer signifi cantly between the two populations, and was not related to the severity of CF. In this study the most prevalent locations were the abd omen for children, and the back, head, and chest for adults. Although pain signifi cantly l imited physical activity, only 15% of patients reported that it caused absenteeism, and 27% reported that it negatively aff ected their family life. Th e mean intensity of great- est pain during the past month, rated on a 0 to 10 visual analog scale was 4.9 (2) (mean [stan dard deviation)) for children and 6 (2) for adults. Only 40% and 50%, respectively, of thos e with pain reported the use of analgesic treatment, mainly paracetamol. At least one episo de of procedural pain during the previous month was reported by 85% of children and 78% of adults. Th is study dem- onstrates the high incidence of undertreated pain in CF patients t hroughout their lives and indicates the need for a thorough assess- ment of pain in childre n with CF. Pain in neuro \201 bromatosis Neurofi bromas typically involve the skin, but may also be s ituated along peripheral nerves and blood vessels or within viscera, and can produce pain i n children (Sahin, 2011 ). Th e lesions characteristically appear during adolescence as sma ll rubbery lesions with a slight dis- colouration of the overlying skin. Neurofi bromas may be associated with swelling and local pain ( \200\230pins and needles \200\231 or \200 \230shooting \200\231 pain) and dysaesthesia in the nerve distribution. Plexiform neurofi b ro- mas are oft en present at birth and frequently located in the orbital or temporal regio n of the face, result from diff use thickening of nerve trunks (Sahin, 2011 ). Plexiform ne urofi bromas may produce overgrowth of an extremity and the deformity of the corresponding bone may cause pain.