Management of chronic pain in children and young people: summary

4. Pharmacological management

4.1 Background

Pharmacological management in children forms a small part of a multidisciplinary strategy (Section 10: Paediatric Pain Pathway). It should be recognised that pharmacological management alone is unlikely to provide the best outcome for patients. In the course of developing this guideline it was apparent that, in contrast to the adult population, there is little high quality evidence of efficacy in the paediatric population. There may be several reasons for this, including the ethical challenges of carrying out randomised controlled trials in this population [29]. As a result, many of the treatments used are out with their marketing authorisation (“off label use”). Such use should be supported by appropriate evidence and experience. “Prescribing medicines outside the conditions of their marketing authorisation alters (and probably increases) the prescribers’ professional responsibility and potential liability” [30].

The General Medical Council ( GMC) [31] recommends that when prescribing a medicine off label, doctors should:

• Be satisfied that such use would better serve the patient’s needs than an authorised alternative (if one exists).

• Be satisfied that there is sufficient evidence/experience of using the medicines to show its safety and efficacy, seeking the necessary information from appropriate sources.

• Record in the patient’s clinical notes the medicine prescribed and, when not following common practice, the reasons for the choice.

• Take responsibility for prescribing the medicine and for overseeing the patient’s care, including monitoring the effects of the medicine.

Non-medical prescribers should ensure that they are familiar with the legislative framework and their own professional prescribing standards.

Although many of the medications used in the management of chronic pain are used off label – information regarding adverse effects and dosing can be obtained from the British National Formulary for Children ( BNFC) [32].

Table 1: Suggested approach to using pharmacological treatment children

Step 1	Assess suitability for pharmacological therapy
Step 2	Start trial of analgesic medication (including dose titration if required)
Step 3	Monitor outcome of trial – continue if benefit; stop if unacceptable side effects or limited pain relief
Step 4	Planned reassessment; at least annually, more frequently if dose changes +/− adverse effects

4.2 Non-opioid analgesics

4.2.1 Simple analgesics

There is paucity of evidence specifically related to the use of simple analgesics in children with chronic non-malignant pain. Aspirin is not recommended for use in children, because of the risk of Reye’s Syndrome [33-35]. Other long term side effects of NSAIDs in children have limited evidence, despite extensive study in adults [11].

A Cochrane review found 4 studies of NSAIDs, only one of which was of high quality. This demonstrated short term pain reduction using naproxen in patellofemoral pain syndrome [35, 36]. In a review of the management of children with sickle cell disease piroxicam was found to be superior to aspirin for treatment of pain, although this study was of low quality [37] (see also previous paragraph about the use of aspirin).

A meta-analysis of 18 RCTs compared ibuprofen to acetaminophen (paracetamol) for treatment of pain (mainly acute pain, with a small number of chronic pain conditions) in children [38]. Ibuprofen was superior to acetaminophen for short term treatment of pain (i.e. immediately after surgery, but not the days following).

4.2.2 Topical analgesics

There is no high quality evidence relating to either lidocaine patches or capsaicin in the management of chronic pain in children. There are a small number of case series where lidocaine patches have been used, and were found to be a safe, effective method for improving patient functionality [39-41].
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There is limited experience of capsaicin therapy in children, as it can cause localised pain during treatment. There is a single case report of the efficacy of capsaicin in the treatment of a case of erythromelalgia [42].
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4.2.3 Anti-convulsants

There was no high quality evidence to support the use of anti-convulsant drugs in children and young people with chronic pain.

One RCT compared the effectiveness of amitriptyline with gabapentin in the treatment of neuropathic pain in children [43]. This was a well-designed study, but only limited conclusions could be drawn in view of the small number of patients studied. 34 patients with neuropathic pain aged between 8 and 17 years were randomised to receive either gabapentin 300mg tds or amitriptyline 10mg at night. Both groups received physiotherapy and psychological therapy. At 6 weeks, the reduction in pain score ( MID, a decrease in pain of 1 or more) in the amitriptyline group was 6 (46.2%) and 9 (60%) for the gabapentin group. Although there was no statistically significant difference between the two drugs ( p= 0.71 for complete cases and p= 0.73 for all cases).
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In reported case series the most frequently used anticonvulsant drug is gabapentin – which has been used as part of a multi-modal approach to treat Complex Regional Pain Syndrome ( CRPS), neuropathic pain in Fabry disease, orchialgia, and distress behaviours in children with severe neurological impairment [44-46]. In children with CRPS, 70% required adjuvant medications (amitriptyline and/or gabapentin) for pain relief and to enable them to participate in physiotherapy. A high percentage of children (92%) had complete resolution of symptoms using this treatment regime (mean=15.4 weeks [range, 3 days to 64 weeks]), but 40% required treatment as a hospital inpatient and 20% had a relapse episode [47]. In the study of children with refractory orchialgia, eight children (57%) treated had resolution of pain, with 50% of those treated with medications alone responding (two to gabapentin and a tricyclic antidepressant, one to gabapentin alone); and five out of eight (63%) treated with medications and then nerve block (ilioinguinal-iliohypogastric block) responding [44]. Of the 22 children with severe impairment of the central nervous system that were treated with gabapentin 21 (91%) had a significant decrease in symptoms [45]. The mean gabapentin dose for children five years of age or less (n=11) was 50 mg/kg/day (95% CI 45-56) compared to children older than 11 years (n=11) with a mean dose of 36 mg/kg/day (95% CI 34-38). No serious adverse events were reported.

Efficacy of pregabalin is described in a case series of children with neuropathic pain secondary to chemotherapy and one small case series of children with Complex Regional Pain Syndrome ( CRPS) [48]. Following their diagnosis of CRPS, 5 patients were administered gabapentin at a dose of 30mg/kg/day, and 2 patients were administered pregabalin at a dose of 150-300mg/day. Pharmacological treatment lasted between 3 and 6 months. All patients participated in physiotherapy, first with passive mobilisation and then with active mobilisation. The authors noted that the 5 patients responded well to both pregabalin and gabapentin.
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There is limited evidence regarding the adverse effects arising from the use of antiepileptic drugs in children and young people with chronic pain, however there is extensive published evidence arising from their use in the management of epilepsy [49]. The commonest side effects of gabapentinoids (including pregabalin) are sedation, nausea and an increase in appetite in children and young people.

In the face of limited evidence of efficacy, the incidence of adverse effects plays a major role in the decision to use anti-convulsant drugs and in the choice of drug. Of the commonly used anti-convulsant drugs gabapentin and pregabalin have the most favourable adverse effect profile [50].

It should be noted that anti-convulsants are not licensed for the management of neuropathic pain in children, however there is a wide body of experience in using these drugs for both epilepsy and pain in children.

4.2.4 Anti-depressants

There is one good quality systematic review of the use of anti-depressants for chronic pain in children [51], which found a lack of high quality studies in this area. Two RCTs were identified, using between 10-30mg of amitriptyline for a maximum of 8 weeks for children with functional gastrointestinal disorders. Amitriptyline did improve quality of life scores by 15% (p=0.007). There are no long term trials evaluating the effectiveness of amitriptyline for pain in children.

There is no evidence supporting the use of other antidepressant medications in children and/or young people for the treatment of pain including selective serotonin reuptake inhibitors ( SSRIs) and serotonin–norepinephrine reuptake inhibitors ( SNRIs) [52].

Based on clinical experience, amitriptyline can have a favourable risk benefit profile when used in low dose in children and young people with a range of chronic pain conditions. The dose should be titrated up to a maximum of 0.5 mg/kg/day over a two to three week period and to benefit, assessed up to six weeks after starting.

Adverse effects using this regimen are usually cognitive behavioural interference and occasionally weight gain. It is advisable to perform a routine electrocardiogram ( ECG) before commencing treatment, and to withhold treatment if an abnormal corrected QT ( QTc) interval is present.
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4.2.5 Non-standard analgesics

There have been several systematic reviews identifying small studies with limited power [53-55]. Specific interventions in the literature search were ketamine, cannabinoids, baclofen, diazepam and clonidine.

There is limited evidence (three RCTs of two small populations) of benefit of intrathecal baclofen with pain reduction as a primary outcome in children with cerebral palsy [53].
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Pain management was measured as a secondary outcome in children with cerebral palsy treated with botulinum toxin. There was no evidence of any benefit of this treatment on pain.
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There is limited evidence of effectiveness of oral alendronate in management of bone pain in osteogenesis imperfecta, but not other bisphosphonates.
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One systematic review on analgesia for functional abdominal pain showed low grade effect of famotidine, cyproheptadine and peppermint oil [54]. Famotidine may only be of benefit in dyspepsia. This was probably the least robust systematic review, as a number of issues related to search strategies were not mentioned.
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Another systematic review on recurrent abdominal pain suggests: pizotifen may be of particular benefit in the treatment of abdominal migraine; famotidine in dyspepsia; peppermint oil in irritable bowel syndrome [55].
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There is no good quality evidence of effect of ketamine, cannabinoids, oral baclofen, diazepam or clonidine in managing chronic pain in children.

4.3 Opioids

In the management of chronic pain in adults, the use of opioids has increased significantly over the last 10-20 years, with increasing concerns about harm from long term use [56]. There is a considerable body of published evidence on using opioids in chronic pain in adults, but this needs to be balanced with concerns that approaches to study design may overestimate the treatment effect [57-59], and an absence of studies examining the effectiveness of long term use. Potential harms include misuse, overdose, endocrine dysfunction, poorly understood effects on the immune system, and fracture [56].

In the paediatric literature, there is very limited evidence for the use of opioids in chronic pain. Identified problems include lack of control groups and small sample sizes [60].

A systematic review, with a somewhat limited search of available databases, of pharmacological management of chronic abdominal pain in children found no studies using strong opioids [51].
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An extensive literature search of published case reports, found a few studies related to chronic opioid use, and is of limited value [61] for this guideline. While the Cochrane review, of opioid switching, used high quality methodology and did include searches for paediatric use, only 2 studies including a paediatric population were identified (from 1965 and 1988) [62]. One of those only had 2 participants <18 and one focussed on acute use in the management of burns.

A recent comprehensive review of the management of sickle cell disease in children did include the use of opioids for chronic pain management. No good quality studies were identified, and the recommendations were based on expert opinion [63].

There have been no studies on the use of compound analgesics in children. MHRA guidance is not to use codeine in children below the age of 13. It should only be used in older children and young people, and only if other analgesics are ineffective.
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Pharmacological Management Recommendations

As noted at the start of this section, there was a paucity of high quality evidence in this area. Unless otherwise stated, these recommendations are based on the consensus opinion of the expert group.

Prior to any prescribing, the licensing status of a medication should be checked in the summary of product characteristics ( SPC). The prescriber must be competent, operate within the professional code of ethics of their statutory bodies and the prescribing practices of their employers [15].

• Pharmacological treatment should only be started after careful assessment. If being used, it should be part of a wider approach utilising supported self-management strategies within the context of a multidisciplinary approach.

• If pharmacological therapy is being used, then there should be regular review; There should be planned reassessment of ongoing efficacy and side effects. Treatment should only be continued if benefits outweigh risks. From a pragmatic perspective this should be a minimum of once per year, to assess continued benefit in terms of pain relief and improvement in function and/or quality of life.

• Paracetamol and non-steroidal anti-inflammatory drugs ( NSAIDs) should be considered in the treatment of chronic non-malignant pain in children and young people. Use should be limited to the shortest possible duration, such as during acute or chronic pain episodes.

• Topical NSAIDs should be considered for treatment of children and young people with localised, non CRPS and non-neuropathic pain.

• 5% lidocaine patches should be considered in the management of children and young people with localised neuropathic pain, particularly when aiming to improve compliance with physiotherapy regimes. They are well accepted, with a low incidence of side effects, restricted to occasional hypersensitivity reactions.
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• Antiepileptic drugs could be considered as part of a multi-modal approach in the management of children and young people with neuropathic pain:

• Gabapentin should be considered as first line anti-convulsant (specialist use only). It should be used in the lowest effective dose, with ongoing monitoring for efficacy and adverse effects.

• Pregabalin could be considered as a second line anti-convulsant drug if gabapentin is not tolerated or is ineffective (specialist use only).

• Low dose amitriptyline should be considered in the treatment of children and young people with functional gastrointestinal disorders.
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• Low dose amitriptyline should be considered in the treatment of children and young people with chronic daily headache, chronic widespread pain and mixed nociceptive/neuropathic back pain.
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• If amitriptyline is effective but particularly sedative in an individual, nortriptyline should be considered as a less sedating alternative.

• Bisphosphonates should be considered in the management of children and young people with osteogenesis imperfecta who have bone pain.

• Intrathecal baclofen should be considered for reducing spasticity related pain in children and young people with cerebral palsy.

• In children and young people with recurrent abdominal pain pizotifen should be considered for abdominal migraine; famotidine for dyspepsia; and peppermint oil forirritable bowel syndrome.

• Opioids and compound analgesics containing opioids are rarely indicated for chronic pain because of their adverse effect profile. Be aware of MHRA advice on codeine. Strong opioids should be used with caution and only with specialist advice or assessment.

• Use of opioids should be for as short a time as possible with regular review and monitoring of efficacy and side effects.

• The use of codeine is not recommended in children under the age of 12 ( MHRA), as it can be associated with a risk of opioid toxicity and respiratory side effects. In general it should also be avoided in adolescents, particularly if they have respiratory problems and individuals known to be CYP2D6 rapid metabolisers should also avoid codeine. Caution is also needed with tramadol use due to genetic variability in metabolism, and production of active metabolites.