DÄ internationalArchive28-29/2008Pain Therapy in Children and Adolescents

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Pain Therapy in Children and Adolescents

Dtsch Arztebl Int 2008; 105(28-29): 511-22. DOI: 10.3238/arztebl.2008.0511

Zernikow, B; Hechler, T

Introduction: In children, acute pain occurs predominantly during infectious illnesses or after surgery. Chronic pain, especially headache and abdominal pain, is becoming increasingly common among children and adolescents.
Methods: Selective literature review, also including evidence-based guidelines and recommendations.
Results: Simple self-reporting and behavioral pain scales are easy to use to assess the intensity of acute pain. To evaluate chronic pain, on the other hand, more complicated, multi-dimensional instruments are necessary (e.g., semi-structured interviews). The most commonly used analgesics are ibuprofen and paracetamol (acetaminophen). When paracetamol is used, its narrow therapeutic window should be kept in mind. Perioperative pain should be treated with balanced analgesia involving a combination of non-pharmacological treatment strategies, non-opioid drugs, opioids, and regional anesthesia. Chronic pain in children can only be treated successfully over the long term with multidisciplinary team intervention based on this biopsychosocial model.
Discussion: Pain not only causes children momentary suffering but also threatens to impair their normal development. Therefore, every effort should be made to prevent pain and to treat it effectively once it arises.
Dtsch Arztebl Int 2008; 105(28–29): 511–22
DOI: 10.3238/arztebl.2008.0511
Key words: pain, children, adolescents, pain scale, medication, treatment
LNSLNS In children, acute pain occurs predominantly during infectious illnesses, painful interventions or after surgery (e1). Chronic pain generally takes the form of headache and abdominal pain, usually with several reported pain locations (1, e2). In this article the authors confine themselves to the most common painful conditions. The learning goals are:

- Differentiating the various presentations and causes of pain
- Becoming familiarized with assessment tools and measures for assessing pain in children of all age groups (infants to adolescents) with acute and chronic pain
- Internalizing the principles of pain therapy adapted to children's age and type of pain.

A separate article devoted to painful interventions will be published at a later date.

The methodological basis of this article was a selective literature review mainly in the Medline database (via PubMed), confined to original articles in German and English, systematic reviews, and evidence-based meta-analyses. The Cochrane Database was also consulted. Unless otherwise indicated, the evidence level is stated as specified by the Oxford Centre of Evidence-based Medicine (Version: May 2001) (www.cebm.net) (table 6 gif ppt).

Acute pain
A large number of acute diseases of childhood (otitis media, pharyngitis, burns, aphthous stomatitis, etc.) are associated with pain. Pain and fever are the commonest causes of an unscheduled pediatric consultation (e3). Almost half the children suffering from otitis media experience severe pain; the mean pain score is 7.5 on a visual analog scale of 0 to 10 (VAS 0–10); 0 = no pain, 10 = maximal pain) (e4). The mean duration of pain can be significantly, but only inconsiderably reduced by antibiotic treatment: from 3.3 to 2.8 days (e5). Antibiotic therapy has little influence on pain intensity in the first 24 hours. Regardless of whether it is decided to treat the child with antibiotics, additional analgesic therapy, for example with ibuprofen, should be initiated for a variable period of one to seven days (recommendation level A) (2). Severe acute pain is also experienced postoperatively. Compared to adults, pediatric patients receive fewer and/or incorrectly dosed analgesics in daily routine (e1). Severe pain experiences in childhood can – even if they cannot subsequently be consciously recalled – lead via the development of a pain memory to unusual sensory processing of pain and altered behavioral patterns persisting well beyond convalescence. If adequate pain prevention is neglected in a single painful intervention, this results in higher analgesic requirements, increased stress and pain as well as a greater proportion of failed analgesia and sedation in subsequent interventions (2).

Chronic pain
Chronic and recurrent pain is a frequent phenomenon during childhood (1, e1, e2) and may be associated with increased anxiety and depression, a restricted level of physical/psychosocial functioning, and frequent school absenteeism (e6). The parents of the affected children are frequently under severe emotional stress and have a tendency to exhibit pain exacerbating reactions (e7, e8). Persisting pain during childhood predisposes towards the development of chronic pain in adulthood (3, 4, e9e13).

Pain assessment
Pain is a subjective phenomenon. Verbal self-reporting is therefore the gold standard for qualitative and quantitative pain measurement both for children of school age and adults (recommendation level B) (5, e14). For pain perception see ebox 1 (gif ppt).

Newborns, infants and young children: The Childhood Discomfort and Pain Scale (KUSS, Kindliche Unbehagen- und Schmerz-Skala) is suitable for assessing postoperative pain in non-mechanically ventilated newborns up to the end of the fourth year (table 1 gif ppt) (6).

Preschool and school children: The KUSS can be used in children without knowledge of German, whose general or linguistic development is delayed, or who are situationally impaired by anxiety. Depending on the developmental status and previous experience, a face pain scale for self rating should be used in children from five years of age (figure gif ppt). Of all the face pain scales, preference should be given to those which are free of emotional content. A face with tears running down can have different meanings; younger children may possibly use this variant to express high pain intensity, while older children do not wish to cry despite having pain – whether because of cultural or family values – and therefore report falsely low values. A laughing face at the beginning of the scale may possibly result in a false high pain score because sick children even without pain rarely see themselves as "happily" laughing. The "Faces Pain Scale – Revised" (7) shows good psychometric characteristics and is most suitable for this age group (8, e15).

Chronic pain: Questionnaires record further pain dimensions such as pain quality, concomitant symptoms, pain-inducing/exacerbating conditions, pain related impairment, emotional distress, quality of life, pain related coping, and self rating of therapy related improvement. Pain relevant factors in the social environment (family, kindergarten, school) are components of the interview guide. For younger children or when there is a wish for additional information, the parent's reported information is also included. For chronic pain, it is indispensable under diagnostic and therapeutic aspects to keep a pain diary designed suitably for children (e14).

Postoperative pain therapy in children and adolescents
Younger children perceive the same injuries as more painful than older children (e16). Multimodal preventive and therapeutic concepts for perioperative pain integrate psychological, pharmacological, and physical techniques (immobilization etc.). The best basis for ensuring effectiveness of pain therapy is good psychological preparation by provision of age-appropriate information.

Principles of non-pharmacological treatment
The purpose of psychological interventions is to prevent children developing anxieties and to beneficially influence pain experience through cognitive and emotional processes. Several methods are indispensable for this purpose:

- Since situational factors influence children's pain experience to a particular degree, optimal background conditions such as age-appropriate briefing, procedures without long waiting times, and child-appropriate room design are important.
- To reduce or prevent anxieties and negative emotional stress factors, cognitive and behavioral therapeutic methods such as age-appropriate education, breathing exercises, role playing, external attention directing or imaginative techniques – adjusted to the individual situation – are to be included (5, e17) (recommendation level A for individual psychological interventions for painful procedures).

Principles of pharmacological treatment
Therapeutic administration of placebos in response to children's acute expressions of pain are not generally productive and ethically highly questionable (see ebox 2 gif ppt). In non-sedated children, intramuscular and subcutaneous injections are to be strictly avoided. Depending on age and culture, rectal administration is often unwelcome. Plasma level concentrations and onset of action – of paracetamol for example – are unpredictable after rectal administration. The absorption of orally administered medications may be delayed in the immediate postoperative period. The intravenous administration of analgesics allows rapid titration according to pain in the recovery room. In the immediate postoperative period on the ward, analgesics should be given according to a fixed time schedule ("by the clock") and additionally on demand – for a variable period depending on the scale of the operation. Analgesics should then be administered according to demand based on the pain score.

Monitoring: Standardized monitoring and documentation protocols are recommended for this purpose. After titration to the required dose, a pain measurement should be performed every two to four hours (at rest and during exercise) with continuous infusion of analgesics.

Analgesics
Modern evidence-based perioperative analgesic regimens are stratified according to the scale, localization, and extent of the operation. They often comprise a combination of regional anesthesiological interventions and systemically acting analgesics (balanced procedure, recommendation level A to C depending on the operation studied). The evidence situation is essentially unsatisfactory in this indication.

Non-opioids
The choice of non-opioids is based on the pathophysiology of the pain and on contraindications. For inflammatory pain, non-steroidal anti-inflammatory drugs (NSAIDs) are used, for spasmodic abdominal pain metamizole and if there is an increased hemorrhagic risk, paracetamol or metamizole. A comparison of the two most commonly used non-opioids paracetamol and ibuprofen is provided in table 2 (gif ppt).

Paracetamol: Paracetamol (PCM) has no clinically relevant inhibitory effect on platelet aggregation. It has no anti-inflammatory component. The adverse effects typical of non-steroidal anti-inflammatory drugs, such as gastrointestinal mucosal injury, are absent. Paracetamol is hepatically glucuronidated and/or sulfated. Overdose results in formation of the highly toxic N-acetyl-p-benzoquinone imine (NAPQI). Genetic changes (polymorphisms of CYP2E1; autosomal recessive inherited deficit of glutathione synthesis) may make affected children more susceptible to the paracetamol associated hepatotoxicity.

PCM is approved for use from birth onwards. The analgesic potency of paracetamol is rated by many authors as lower than that of ibuprofen or other NSAIDs (5, e18). Postoperatively, paracetamol monotherapy is only weakly effective (e19). Dose recommendations for paracetamol are given in table 3 (gif ppt).

Non-steroidal anti-inflammatory drugs (NSAIDs): The NSAID most widely used in pediatrics is ibuprofen (table 4 gif ppt). Like all non-selective NSAIDs, it inhibits cyclooxygenase (COX) type I and II and secondarily also platelet aggregation. For interventions with an increased hemorrhagic risk (tonsillectomy, large wound areas etc.) and in patients with hemorrhagic tendency a careful risk assessment is required. The influence of COX I and II inhibitors on the incidence of relevant bleeding after tonsillectomy has not yet been conclusively determined: a Cochrane analysis concludes that the risk of relevant post-tonsillectomy bleeding is not increased by NSAIDs (9, e20e22). Children rarely develop gastrointestinal mucosal injury and nephrotoxicity after short-term ibuprofen therapy (less than seven days). These adverse effects do not occur more often than with paracetamol. Individual cases of acute renal failure have been reported when dehydrated children received NSAIDs. In children with mild bronchial asthma, the risk of an allergic reaction to NSAIDs is classified as low. Ibuprofen is only approved for use in children older than six months since in younger infants the risk of reduced cerebral or renal blood flow may be increased.

Metamizole: Because of its spasmolytic properties metamizole is particularly suitable for visceral pain or colicky pain. Caution is advised in patients with a history of asthma or allergies and when the cardiovascular situation is unstable. During intravenous therapy, a considerable fall in blood pressure and even shock can occur due to hypersensitivity reactions or allergies.

Metamizole should only be administered as a short infusion and always with close monitoring of blood pressure values. More useful than repeated short infusions is a long-term infusion with a dosage of 2.5 to 3.0 mg/kg/h. Metamizole is – depending on the route of administration and the product – approved for use from the age of three months onwards. A risk assessment for agranulocytosis in children receiving metamizole therapy is not possible at present – only one such case has been reported to date (10)

Opioids
Newborns, infants, and children with pre-existing cerebral impairment react with particular sensitivity to opioids, which therefore have to be initiated at low doses and titrated upwards slowly until maximal control of the symptoms amenable to pharmacotherapy is achieved. Besides respiratory depression and sedation, the same adverse effects are essentially seen in children as in adults (nausea, vomiting, constipation, pruritus, urinary retention, lowered seizure threshold). The risk of dependence is to be classified as low. An extensive literature search failed to disclose a single documented case. As opioids for moderate to severe pain, tramadol and tilidine, for severe to very severe pain especially morphine and, if this is poorly tolerated by certain individuals, buprenorphine, hydromorphone, and oxycodone are used. Despite scant scientific evidence, piritramide is widely used in Germany (Recommendation level for postoperative use of opioids [also as patient-controlled analgesia, PCA] depending on the operation: A to C) (5).

Tramadol: Tramadol has not only an opioid receptor mediated action but also serotonergic and adrenergic mechanisms of action (11). After a saturation dose, a continuous long-term infusion is more suitable because of its better tolerability. Especially the combination with metamizole has proved successful particularly for visceral pain. Tramadol is not subject to the German Federal Narcotics Act.

Tilidine/naloxone: Tilidine/naloxone can be used orally in older children in the later postoperative course. Tilidine is not subject to the provisions of the German Federal Narcotics Act.

Morphine: Morphine is the opioid of choice for pediatric use. Starting doses are listed in table 5 (gif ppt). The safety and efficacy of continuous intravenous administration of opioids for pain management are well established for all age groups (e1).

Morphine PCA: Patient-controlled analgesia (PCA) can be used in children aged six years or more (5, e14). Postoperatively, a basic infusion of 4 µg/kg/h morphine is not associated with an increased rate of adverse effects (e23). Pediatric opioid PCA requires special logistics and regular monitoring of vital signs. Loading doses are shown in table 5, the lockout time – loading dose demand does not result in a loading dose but is recorded by the PCA pump – is usually ten minutes.

Piritramide: Because of its acidic pH, piritramide should not be given together with other drugs through the same intravenous line. The dosage corresponds to that of morphine (table 5).

Pethidine: The use of pethidine is no longer recommended because of its long half-life and the seizure threshold lowering metabolite norpethidine. Norpethidine can cumulate during prolonged pethidine use and postoperatively (11, e24, e25).

Regional anesthesia and analgesia
In children, regional anesthesia should be carried out under deep sedation or general anesthesia (table 6). The Pediatric Anesthesia Working Group of the German Society of Anesthesiology draws attention to the fact that routine clotting analyses are not required in healthy children before applying regional anesthesia. Ropivacaine appears to be the local anesthetic of first choice for epidural/caudal analgesia because of its low cardiotoxicity, low incidence of motor blocks, and favorable pharmacokinetics on continuous administration (5, e26). In children, respiratory and sedation monitoring should be practiced for at least 24 h after epidural opioid administration.

Chronic and recurrent pain
Headache is one of the commonest pediatric health problems (12, e2). In Germany an estimated 1 000 000 school days are missed every year because of headache.

Migraine: 5% to 10% of all 7- to 15-year-olds suffer from migraine (in most cases without aura). In the last 20 years the prevalence of migraine among 7-year-olds has risen from 1.9% to 5.2% (e27). The diagnostic criteria of the International Headache Society (IHS) define migraine without aura as follows (13).

- At least five attacks fulfil the following criteria
- Duration of attack 4 h (children 1 h) to 72 h
- Headache fulfils at least two of the following criteria
  – Unilateral location (children also: bilateral frontal/temporal)
  – Pulsating
  – Moderate to severe pain intensity
  – Exacerbation on physical activity
- Headache is accompanied by at least one of the following symptoms
  – Nausea and/or vomiting
  – Photophobia and phonophobia.

Tension-type headache: Up to 25% of all children aged 7 to 15 years complain of episodic tension-type headache. In contrast to migraine, the pain attack may last from 30 minutes to 7 days and is of lower intensity (13). 5% of the children complain of nausea, 15% of photophobia/phonophobia respectively during the headache phase (e28, e29).

Diagnostic procedures for headache
Recurrent headache in childhood can usually be diagnosed on the basis of the medical history and physical examination (14). Electroencephalography (EEG) is only recommended if associated symptoms suggest the presence of a cerebral convulsive disorder (14). A cranial MRI (magnetic resonance imaging) scan is only indicated in exceptional cases (ebox 3 gif ppt).

Pharmacological therapeutic approaches for acute migraine attacks: Treatment of migraine attacks is stratified according to severity, duration, and accompanying symptoms (12). Single-agent preparations are to be preferred and administered in sufficiently high dosages. Ibuprofen is superior to paracetamol; a direct comparison shows that complete pain relief after two hours is achieved twice as frequently with ibuprofen (15). For attacks of headache that are already initially very severe, rapidly progressive, or accompanied by numerous other symptoms and if the primary ibuprofen therapy is ineffective, sumatriptan nasal spray should be used, which is approved in Germany for use in children aged 12 years or more (dose: 10 mg intranasal) (8) (recommendation level A, [8, 12, 16, e30–e33]). Acetylsalicylic acid should only be used from age 12 years onwards because of the risk of Reye's syndrome (e34).

Migraine prophylaxis: The efficacy of multimodal outpatient treatment programs (including elements from cognitive behavioral therapy, relaxation techniques, hypnosis, biofeedback, and endurance training) has been convincingly demonstrated (recommendation level A) (1, 17, 18).

Purely clinical experience shows that a regular life style with sufficient sleep, a balanced diet and adequate fluid intake is helpful. Pharmacological prophylaxis in childhood should only be employed if attack therapy is inadequate and the non-pharmacological prophylactic measures fail (12). Migraine prophylaxis is performed for a period of three to six months keeping a migraine diary and is then interrupted to assess the spontaneous course. The medications are generally titrated upwards from an initial low level and finally tapered out. The most commonly used substances are the beta blocker metoprolol and the calcium channel blocker flunarizine (no beta blockers in patients with asthma) and the anticonvulsant topiramate (recommendation level D, because of conflicting study results [12, 19, e35–e41]).

Treatment options in tension-type headache: In most cases this headache can be treated using non-pharmacological strategies which have to be learned by the child in group or in one-to-one sessions, such as muscle relaxation by the Jacobson method as well as cognitive-behavioral strategies and biofeedback. TENS (transcutaneous electrical nerve stimulation) has proved helpful in open-label studies.

Chronic abdominal pain
The prevalence of chronic abdominal pain among children of school age is 10% to 25% (e42). Apley defines typical chronically recurrent abdominal pain as abdominal pain that occurs episodically at least once a month for at least three months in succession and impairs the child's normal activities (20). At present, chronic abdominal pain is classified according to the Rome III criteria (21) (ebox 4 gif ppt). In more than half of the cases the functional abdominal pain is already primarily associated with other forms of pain such as headache and chest pain.

Children with functional abdominal pain show characteristic features (e42):

- Periumbilical (45%) or epigastric pain (40%) lasting for less than one hour in two thirds of the children and almost always for less than three hours
- Child and parents can almost never name measures that shorten the pain event
- Pain is frequently associated with autonomic nervous symptoms such as pallor and nausea
- Physical examination reveals no abnormalities.

Caution is advised if one of the warning signs mentioned in the box occur (box gif ppt).

Somatic, mental, and social "abnormalities": Many of the children affected show "abnormalities" such as disorders of gastrointestinal motility, carbohydrate malabsorption or positive Helicobacter pylori tests. The presence of positive organic findings, however, has no influence on the long-term course (22). According to the ESPGHAN (European Society for Pediatric Gastroenterology, Hepatology, and Nutrition) Consensus Statement, there is no validated relationship between the Helicobacter infection and chronic recurrent abdominal pain (22). Children with abdominal pain and non-ulcerative gastritis do not benefit symptomatically from HP eradication. Many psychosocial "abnormalities" have been proclaimed for these children and their families. The study results are contradictory, especially in cases where not healthy but chronically ill children and their families were used as reference group.

Bio-psycho-social model
After excluding other diseases by means of medical history and physical examination, the pediatrician can continue searching for "the" cause or interpret the functional pain within the context of a bio-psycho-social model (23, e43): a child's vulnerability in terms of functional abdominal pain is an interplay between organic dysfunction (in these cases especially of the gastrointestinal tract) and psychological factors. Once functional abdominal pain has developed, the recurrent pain experience increases the child's vulnerability, and this all the more, the more clearly the pain is perceived and intensified by the environment. Stressors can be psychosocial or biological in nature (e.g. lactose loading).

Treatment
In several studies on the long term course over 5 to 30 years, the children who formerly suffered functional abdominal symptoms were now suffering considerably more frequently from chronic abdominal pain, other somatic symptoms, and psychosocial disorders (e44). No significantly positive therapeutic results were obtained for functional abdominal symptoms on introducing lactose-free diet or increasing nutritional dietary fiber (24). The course of functional abdominal symptoms can be favorably influenced by strategies such as comprehensive education about the maintenance of chronic pain and learning appropriate pain related coping strategies. Cognitive behavioral therapy combined with training measures for parents are also promising (recommendation level A) (1, e44). Other forms of chronic abdominal pain also benefit from pharmacological therapeutic approaches such as attack therapy with ibuprofen for abdominal migraine.

Somatoform pain disorders
Somatoform pain disorders are dominated by persistent and intolerable pain which cannot be explained in terms of physiological processes (e45). The prevalence of somatoform pain disorder in childhood is 2% to 3% (200 000 affected children in Germany) (e46). For extreme pain-related life impairment, high school absenteeism, concurrent emotional problems or if outpatient therapeutic interventions fail, inpatient multimodal pain therapy is recommended (recommendation level B, evidence level of studies: 3 and 4a [e46, e47]).

Conclusion
Children with acute pain are entitled to adequate, age-appropriate pain evaluation and treatment. Extremely severe acute and recurrent or chronic pain compromises their development. Nationwide health care structures providing adequate postoperative acute pain therapy and multimodal treatment programs for chronic pain are lacking in Germany.

Conflict of interest statement
Mr. Zernikow received lecture fees, remuneration for consultations, and financial support for conference visits from the following companies: AstraZeneca, Aventis, Boots Healthcare, Bristol-Myers Squibb, Cephalon, Grünenthal, Janssen Cilag, Mundipharma, Pfizer, and Reckitt Benckiser.
Ms. Hechler declares that no conflict of interest exists according to the guidelines of the International Committee of Medical Journal Editors.

Manuscript received on 20 November 2007, revised version accepted on 11 June 2008.

Translated from the original German by mt-g.


Corresponding author
PD Dr. med. Boris Zernikow
Vodafone Stiftungsinstitut für Kinderschmerztherapie
und Pädiatrische Palliativmedizin
Vestische Kinder- und Jugendklinik
Universität Witten/Herdecke
Dr.-Friedrich-Steiner-Str. 5
45711 Datteln, Germany
B.Zernikow@Kinderklinik-Datteln.de


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Solutions to the CME questionnaire in volume 21/2008:
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e16. Berde CB, Sethna NF: Analgesics for the treatment of pain in children. N Engl J Med 2002; 347: 1094–113. MEDLINE
e17. Labouvie H, Kusch M, Bode U: Psychologische Interventionen bei akuten Schmerzen im Kindesalter. In: Zernikow B (Ed.): Schmerztherapie bei Kindern. Berlin: Springer 2005; 132–42.
e18. Lönnqvist PA, Morton NS: Postoperative analgesia in infants and children. Br J Anaesth 2005; 95: 59–68. MEDLINE
e19. Mantzke US, Brambrink AM: Paracetamol im Kindesalter: Aktueller Wissensstand und Hinweise für einen rationalen Einsatz zur postoperativen Analgesie. Anaesthesist 2002; 51: 735–46. MEDLINE
e20. Moiniche S, Romsing J, Dahl JB, Tramer MR: Nonsteroidal anti-inflammatory drugs and the risk of operative site bleeding after tonsillectomy: a quantitative systematic review. Anesth Analg 2003; 96: 68–77. MEDLINE
e21. Krishna S, Hughes LF, Lin SY: Postoperative hemorrhage with nonsteroidal anti-inflammatory drug use after tonsillectomy: a meta-analysis. Arch Otolaryngol Head Neck Surg 2003; 129: 1086–9. MEDLINE
e22. Jeyakumar A, Brickman TM, Williamson ME, Hirose K, Krakovitz P, Whittemore K et al.: Nonsteroidal anti-inflammatory drugs and postoperative bleeding following adenosillectomy in pediatric patients. Arch Otolaryngol Head Neck Surg 2008; 134: 24–7. MEDLINE
e23. Doyle E, Robinson D, Morton NS: Comparison of patient-controlled analgesia with and without a background infusion after lower abdominal surgery in children. Br J Anaesth 1993; 71: 670–3. MEDLINE
e24. Morton NS: Management of postoperative pain in children. Arch Dis Child Educ Pract Online 2007; 92: ep14–ep19. MEDLINE
e25. American Academy of Pediatrics: The Assessment and Management of Acute Pain in Infants, Children and Adolescents. Pediatrics 2001; 108: 793–7. MEDLINE
e26. Mazoit J, Dalens BJ: Ropivacaine in infants and children. Curr Opin Anaesthesiol 2003; 16: 305–7. MEDLINE
e27. Sillanpää M, Anttila P: Increasing prevalence of headache in 7-year-old schoolchildren. Headache 1996; 36: 466–70. MEDLINE
e28. Rossi LN, Vajani S, Cortinovis I, Spreafico F, Menegazzo L: Analysis of the International Classification of Headache Disorders for diagnosis of migraine and tension-type headache in children. Dev Med Child Neurol 2008; 50: 305–10. MEDLINE
e29. Özge A, Bugdayci R, Sasmaz T, Kaleagasi H, Kurt O, Karakelle A et al.: The sensitivity and specificity of the case definition criteria in diagnosis of headache: a school-based epidemiological study of 5562 children in Mersin. Cephalalgia 2002; 22: 791–8. MEDLINE
e30. Überall M, Wenzel D: Intranasal sumatriptan for the acute treatment of migraine in children. Neurology 1999; 52: 1507–10. MEDLINE
e31. Winner P, Rothner AD, Saper J, Nett R, Asgharnejad M, Laurenza A et al.: A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents. Pediatrics 2000; 165: 989–97. MEDLINE
e32. Ahonen K, Hämäläinen ML, Rantala H, Hoppu K: Nasal sumatriptan is effective in treatment of migraine attacks in children: A randomized trial. Neurology 2004; 62: 883–7. MEDLINE
e33. Winner P, Rothner AD, Wooten JD, Webster C, Ames M: Sumatriptan nasal spray in adolescent migraineurs: a randomized, double-blind, placebo-controlled, acute study. Headache 2006; 46: 212–22. MEDLINE
e34. Tfelt-Hansen P: Triptans vs Other Drugs for Acute Migraine. Are There Differences in Efficacy? A Comment. Headache 2008; 48: 601–5. MEDLINE
e35. Winner P, Pearlman EM, Linder SL, Jordan DM, Fisher AC, Hulihan J: Topiramate Pediatric Migraine Study Investigators. Topiramate for migraine prevention in children: a randomized, double-blind, placebo-controlled trial. Headache 2005; 45: 1304–12. MEDLINE
e36. Winner P, Gendolla A, Stayer C, Wang S, Yuen E, Battisti WP et al.: Topiramate for migraine prevention in adolescents: a pooled analysis of efficacy and safety. Headache 2006; 46: 1503–10.
e37. Sorge F, De Simone R, Marano E, Nolano M, Orefice G, Carrieri P: Flunarizine in prophylaxis of childhood migraine. A double-blind, placebo-controlled, crossover study. Cephalalgia 1988; 8: 1–6.
e38. Sorge F, Marano E: Flunarizine v. placebo in childhood migraine. A double-blind study. Cephalalgia 1985; 5 (Suppl 2): 145–8. MEDLINE
e39. Ludvigsson J: Propranolol used in prophylaxis of migraine in children. Acta Neurol Scand 1984; 50: 109–15. MEDLINE
e40. Forsythe WI, Gilles D, Sills MA: Propanolol („Inderal“) in the treatment of childhood migraine. Development Medicine & Child Neurology 1984; 26: 737–41. MEDLINE
e41. Olness K, MacDonald JT, Uden DL: Comparison of self-hypnosis and propranolol in the treatment of juvenile classic migraine. Pediatrics 1987; 79: 593–7. MEDLINE
e42. Berger T, Damschen U: Rezidivierende Bauchschmerzen. In: Zernikow B (ed.): Schmerztherapie bei Kindern. Heidelberg: Springer 2005.
e43. Crushell E, Rowland M, Doherty M, Gormally S, Harty S, Bourke B et al.: Importance of parental conceptual model of illness in severe recurrent abdominal pain. Pediatrics 2003; 112: 1368–72. MEDLINE
e44. Weydert JA, Ball TM, Davis MF: Systematic review of treatments for recurrent abdominal pain. Pediatrics 2003; 111: e1–e11. MEDLINE
e45. Remschmidt H, Schmidt M, Poustka F: Multiaxiales Klassifikationsschema für psychische Störungen des Kindes- und Jugendalters nach ICD-10 der WHO. Bern, Hans Huber, 2006.
e46. Dobe M, Damschen U, Reiffer-Wiesel B, Sauer C, Zernikow B: Dreiwöchige stationäre multimodale Schmerztherapie bei Kindern und Jugendlichen mit chronischen Schmerzen. Schmerz 2006; 20: 51–60. MEDLINE
e47. Hechler T, Dobe M, Kosfelder J et al.: Effectiveness of a three-week multimodal inpatient pain treatment for children and adolescents suffering from chronic pain: Statistical and clinical significance. Clin J Pain 2008; in Press.
e48. Halpern SM, Fitzpatrick R, Volans GN: Ibuprofen toxicity. A review of adverse reactions and overdose. Adverse Drug React Toxicol Rev 1993; 12: 107–28. MEDLINE
e49. Rainsford KD, Roberts SC, Brown S: Ibuprofen and paracetamol: Relative safety in non-prescription dosages. J Pharm Pharmacol 1997; 49: 345–76. MEDLINE
e50. Bradley RL, Ellis PE, Thomas P, Bellis H, Ireland AJ, Sandy JR: A randomized clinical trial comparing the efficacy of ibuprofen and paracetamol in the control of orthodontic pain. Am J Orthod Dentofacial Orthop 2007; 132: 511–7. MEDLINE
e51. Ali S, Klassen TP: Ibuprofen was more effective than codeine or acetaminophen for musculoskeletal pain in children. Evid Base Med 2007; 12: 144. MEDLINE
e52. Silver S, Gano D, Gerretsen P: Acute treatment of paediatric migraine: A meta-analysis of efficacy. J Paed Child Health 2008; 44: 3-9. Epub 2007 Sep 14 MEDLINE
e53. Ulinski T, Guigonis V, Dunan O, Bensman A: Acute renal failure after treatment with non-steroidal anti-inflammatory drugs. Eur J Pediatr 2004; 163: 148–50. MEDLINE
e54. Stanford EA, Chambers CT, Craig KD: A normative analysis of the development of pain-related vocabulary in children. Pain 2005; 114: 278–84. MEDLINE
e55. Harbeck C, Peterson L: Elephants dancing in my head: A developmental approach to children's concepts of specific pains. Child Dev 1992; 63: 138–49. MEDLINE
e56. Chen X: Growing up in a collectivistic culture: Socialization and socio-emotional development in Chinese children. In: Comunian AL, Gielen UP, (eds.): International perspective on human development. Lengerich, Italy: Pabst Science Publishers 2000; 331–53.
e57. von Baeyer CL, Marche TA, Rocha EM, Salmon K: Children's memory for pain: Overview and implications for practice. J Pain 2004; 5: 241–9. MEDLINE
e58. Kokki H, Lintula H, Vanamo K, Heiskanen M, Eskelinen M: Oxycodone vs placebo in children with undifferentiated abdominal pain: a randomized, double-blind clinical trial of the effect of analgesia on diagnostic accuracy. Arch Pediatr Adolesc Med 2005; 159: 320–5. MEDLINE
e59. Evers S: Controlled trials in pediatric migraine: Crossover versus parallel group. Curr Pain Headache Rep 2007; 11: 241–4. MEDLINE
e60. Goodenough B, Kampel L, Champion GD, Laubreaux L, Nicholas MK, Ziegler JB et al.: An investigation of the placebo effect and age-related factors in the report of needle pain from venipuncture in children. Pain 1997; 72: 383–91. MEDLINE
e61. Klinger R, Soost S, Flor H, Worm M: Classical conditioning and expectancy in placebo hypoalgesia: A randomized controlled study in patients with atopic dermatitis and persons with healthy skin. Pain 2007; 128: 31–9. MEDLINE
e62. Tait AR, Voepel-Lewis T, Malviya S: Factors that influence parents' assessments of the risks and benefits of research involving their children. Pediatrics 2004; 113: 727–32. MEDLINE
e63. Flor H, Hermann C: Schmerz. In: Flor H, Birbaumer N, Hahlweg K, (eds.): Grundlagen der Verhaltensmedizin. Göttingen: Hogrefe 1999; 249–330.
e64. Raquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams JS, Staiano A et al.: Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology 2006; 130: 1527–37. MEDLINE