Pain Management

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Pediatric pain management in palliative care Julia Downing*,1, Satbir Singh Jassal2, Lulu Mathews3, Hanneke Brits4 & Stefan J Friedrichsdorf5 Practice Points ●●

The 2012 publication of the WHO guidelines for the pharmacological treatment

of persisting pain in children with medical illnesses has been a key step in the ongoing development of pain management in pediatric palliative care, and offers a comprehensive guide for professionals. ●●

The analgesics available for managing pain in children have increased significantly

over the last decade, however the research evidence for efficacy and safety of these drugs is limited. ●●

Most persisting acute pain can be managed utilizing the WHO two-step analgesic ladder.

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Many children in palliative care may have mixed somatic (acute and visceral),

neuropathic, chronic (pain extends beyond expected time of healing) and psychosocial-spiritual pain (total pain). ●●

Advanced pain management usually requires an interdisciplinary approach using a

combination of pharmacology, rehabilitative, integrative (nonpharmacological) and, if available, anesthetic approaches. ●●

Access to medications around the world, in particular opioids such as morphine, remains a barrier to the control of pain in children, thus causing unnecessary suffering.

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The World Health Assembly Resolution on palliative care in May 2014 urges member states to implement recommendations, including improving accessibility to pain management in pediatric palliative care.

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Gaps remain in the evidence base for managing pain, and there is a need for ongoing education and research in the area.

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The optimal way of managing persistent pain in children with medical illnesses is still to be agreed and requires both interdisciplinary and international collaboration.

SUMMARY The management of pain in pediatric palliative care (PPC) is essential. Whilst the field of pain management has developed over the years, much of what is done in PPC is based on anecdotal evidence or adult studies. This review explores recent developments International Children’s Palliative Care Network & Makerere University, Kampala, Uganda Rainbow Hospice for Children & Young People, Loughborough, UK 3 Department of Pediatrics, Calicut Medical College & Institute of Palliative Medicine, Calicut, India 4 Department of Family Medicine, Bloemfontein, South Africa 5 University of Minnesota Medical School & Department of Pain Medicine, Palliative Care & Integrative Medicine, Children’s Hospitals & Clinics of Minnesota, Minneapolis, MN, USA *Author for correspondence: Tel.: +256 712 266 251; [email protected] 1 2

10.2217/PMT.14.45 © 2015 Future Medicine Ltd

Pain Manag. (2015) 5(1), 23–35

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Review  Downing, Jassal, Mathews, Brits & Friedrichsdorf Keywords 

• global • integrative • nonpharmacological • pain • pain assessment • pain guidelines • pain management • pediatric • pharmacological • public

in pain management in PPC, in particular the WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses. Key issues discussed include the definition, assessment, pharmacological and integrative management of pain, availability of medications, education and research. Whilst advances have been made, including publication of the guidelines, significant gaps exist in terms of the evidence base, education and access to essential medications and both interdisciplinary and international collaboration are required to meet these gaps.

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Palliative care for children remains a relatively new concept in many countries, with children who need it, being unable to access care [1] . Over recent years there has been a rapid expansion of palliative care services, yet the need for services far outweighs provision, particularly in lowresource settings. In 2011, a systematic review undertaken with regards to global provision of children’s palliative care [2] found only 5.7% of countries had children’s palliative care provision reaching mainstream provision, with 65.6% of countries having no known children’s palliative care activity. Connor and Sepulveda [3] in their Global Atlas of Palliative Care at the End of Life estimated that 63 children out of every 100,000 will require palliative care at the end of life, with other studies estimating between 32 per 10,000 (UK [4]) and 180 per 10,000 [5] . Children with life-limiting or life-threatening conditions have unique palliative care needs which are different from those of adults [6] , thus in order to provide holistic care for the child and their families, in other words, physical, psychological, social and spiritual, care must be aimed at the individual child and his/her family, regardless of age, diagnosis, where they live, etc. Palliative care, along with the commitment to the relief of pain, has been recognized as a human right [7] . This was appreciated in the International Children’s Palliative Care Network (ICPCN) Declaration of Cape Town in 2009, which states that palliative care for children is a basic human right, and that the ICPCN believe that ‘all children with life-threatening and life-limiting conditions have the right to quality palliative care’ and that ‘holistic family-centered children’s palliative care encompasses individualized assessment, pain and symptom management, psychosocial, spiritual, developmental and bereavement support’ [6] . Similarly the recent Trieste Charter on the Rights of the Dying Child states that they should ‘receive effective treatment for pain, and physical and psychological symptoms causing suffering through qualified, comprehensive and continuous care’ [8] . Thus the importance of providing comprehensive pain management

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in children’s palliative care and keeping abreast with up-to-date relevant literature is essential for all professionals working within the field. A review of the literature on pain management in pediatric palliative care (PPC) since 2009, showed significant development in the field, particularly with relation to the publication of the 2012 WHO guidelines for the pharmacological management of persisting pain in children with medical illnesses [9] . Alongside a discussion of the guidelines, the literature will be reviewed covering the key components of the guidelines, in other words, the definition and classification of pain, assessment of pain, the pharmacological management of pain, availability of medications such as oral morphine, education and research. Finally, integrative management of persisting pain in children will also be discussed. Throughout the paper a global perspective will be provided, and significant advances, ongoing challenges and unmet need will be addressed. The WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses In 2012, the WHO guidelines on pharmacological treatment of persisting pain in children with medical illnesses [9] were published, based on available evidence and extending the mandate beyond cancer to the management of persisting pain in children with medical illnesses [10] . Thus considering conditions such as cancer, major infection, e.g., HIV, arthritis, sickle cell disease, burns and neuropathic pain following amputation [11] . Pain The International Association for the Study of Pain (IASP) define pain as ‘An unpleasant sensory and emotional experience associated with actual or potential tissue damage’ [12] . According to the complete detailed definition, pain is much broader than just physical damage to tissues. Dame Cicely Saunders first used the term ‘Total Pain’ which included the physical, emotional, social and spiritual aspects of pain [13] . Pain is therefore a multidimensional phenomenon

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Pediatric pain management in palliative care  with sensory, physiological, cognitive, affective, behavioral and spiritual components, is subjective, and is experienced by children as well as adults [9] . Whilst it is difficult to provide comprehensive and accurate figures on the extent of pain in children [11] , estimates vary from around 67% of those needing specialist palliative care [14] to all patients with cancer experiencing pain at some stage of their illness [15] . Pain is also seen by parents of children with cancer as one of the most prevalent and distressing symptoms, particularly during cancer treatment itself [16] . Pain experienced by children receiving palliative care is usually related to the disease itself, medical interventions and treatment-related pain. Incidental pain may also be experienced due to co-morbidities experienced by the child [17] . Despite the high incidence of pain, there is general agreement that pain in infants, children and young people is often underestimated and undertreated [18] . This under estimation and treatment of pain in children reflects various persistent misconceptions, e.g.: that infants do not feel pain; they do not remember painful experiences; that children suffer less pain than adults; fears regarding the use of pharmacological agents; that children become addicted to opioids more easily than adults; deficits in knowledge of pain assessment and management; the inability of infants to express their pain, personal values and beliefs [11,18–20] . Classifications of pain Different classifications for pain exist mainly according to its origin, duration or site. According to its origin (pathophysiology) pain can be nociceptive (acute or visceral), neuropathic or mixed. When the cause of the pain is not determined, it is classified as idiopathic pain. Nociceptive pain occurs with direct stimulation of pain receptors (e.g., skin, mucosa, muscles or internal organs) and neuropathic pain when there is structural damage to the nerve itself. Because of the different types of tissues involved, treatment will differ for different types of pain. According to its duration, pain can be classified as either acute or chronic. No specific duration is stipulated to distinguish between the two, however the IASP define chronic pain in adults as “a recurrent or continuous unpleasant sensation that is categorized by length of duration: persisting for 1 month, 1 to 6 months or greater than 6 months” [21] . In children, chronic pain is usually considered pain existing ‘beyond the

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expected time of healing’. Pain can also occur as intermittent (e.g., migraine), incident dependent (e.g., specific movement) or breakthrough pain. The classification of pain according to its location is often not very helpful in the management of the pain, but might be useful to assist the child to locate and identify the pain. Whilst the IASP definition of pain has been widely adopted [12] , their definition of chronic pain [21] has not been, and definitions of acute and chronic pain are based on arbitrary time frames and do not address distinctions based on physiological and pathological causes relevant for its treatment, e.g., neuropathic and nociceptive pain. Hence the revised 2012 WHO guidelines [9] utilize the phrase ‘persisting pain in medical illnesses’ to try and encompass these differences [11] . Pain assessment In order to manage pain comprehensively, it is important to first assess the pain accurately by means of a good history and examination, to treat the pain according to treatment principles and to monitor the outcome of the treatment and adjust if necessary. The guidelines suggest that pain assessment should involve the child, the parents or caregivers and the health professional. It should involve a detailed pain history, a physical examination, diagnosis of the cause and measurement of severity using an age appropriate tool. Suggested questions to help in the assessment can be found in Box 1. Neale [17] suggests when assessing pain in an adolescent with cancer, questions can be structured around the PQRST method (Palliative/ provoking, Quality, Radiation, Site/symptoms, Timing/ triggers), thus focusing questions on the specificities of the pain. An age-appropriate assessment scale should be used to monitor pain management. Self-report measures are preferred and provide the most valid pain score, however not all children will have the cognitive and language skills to enable them to complete a self-report measure, thus behavioral indices will be evaluated in order to assess pain  [17–20,22–23] . There are many different pain assessment tools for babies and children that have been developed and are used on a regular basis. Srouji et al. [18] in their review on pain in children identified 19 different pain assessment tools for different age groups, discussing the different attributes of each. Similarly, Chuaretti et al. [19] when looking at current practice and recent

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Review  Downing, Jassal, Mathews, Brits & Friedrichsdorf Box 1. Summary of questions for assessment [9p29]. ●● What words do the child and family use for pain? ●● What verbal and behavioral cues does the child use to express pain? ●● What do the parents and/or caregivers do when the child has pain? ●● What do the parents and/or caregivers not do when the child has pain? ●● What works best in relieving the pain? ●● Where is the pain and what are the characteristics (site, severity, character of pain as described by the child/parent, e.g., sharp, burning, aching, stabbing, shooting, throbbing)?

●● How did the present pain start (was it sudden/gradual)? ●● How long has the pain been present (duration since onset)? ●● Where is the pain (single/multiple sites)? ●● Is the pain disturbing the child’s sleep/emotional state? ●● Is the pain restricting the child’s ability to perform normal physical activities (sit, stand, walk, run)? ●● Is the pain restricting the child’s ability/willingness to interact with others, and ability to play?

advances in pediatric pain management identified key tools for each age group. Whilst discussing different tools, the WHO guidelines package provides copies of tools that can be used such as the faces scale and a visual analogue scale. However, it is important that these tools be utilized within a comprehensive assessment process. The literature suggests that although there is a lot of information with regards to pain assessment, it is often not being applied effectively, and assessment needs to take into consideration issues of age, developmental level, cognitive and communication skills, previous pain experiences and associated beliefs [18,19] . However, appropriate assessment of pain can be undertaken through a comprehensive assessment and helps to improve comfort, prevents the under treatment of pain in children and creates a common language and communication amongst health professionals [19] . Pharmacological management A major change from the previous WHO guidelines is the change from the use of a 3-step analgesic ladder to a two-step ladder with the omission of ‘weak opioids’ (namely, codeine) as 2 (Figure 1) . This is an approach that is already being promoted in the literature and is being recommended where the appropriate medications are available [19–20,23–26] . In 2007, the WHO Guideline Review Committee adopted the principle that all guidelines should be developed to comply with internationally accepted best practices and evidence [9] . The Guideline Development Group assessed drugs and drug combinations, administration routes, duration of action and adjuvant therapies

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regarding quality of evidence, risks and benefits, cost, values and acceptability and feasibility (as appropriate) for all drugs used in children. The weak opioids in step 2, codeine and tramadol, did not meet all the criteria for inclusion in the guideline. The Guideline Development Group concluded that there is no robust data to support the safe use of codeine in children. The effects of codeine are unpredictable and therefore pose a safety risk. Tramadol is not registered for use in children below 12 years of age in some countries with current insufficient data to support its effectiveness and safety in children. The benefit of having effective pain control with morphine outweighs the benefits of codeine/tramadol in this age group [9] . A view that has been supported within the recent literature, stressing the need for research into the utilization of medications such as Tramadol in children [11,14,19,23–25] . The guidelines stress that the following principles should continue to be taken into consideration when prescribing medicine for the treatment of pain [9] : ●● By the ladder, using the new two-step approach for children; ●● By the clock, using regular dosage intervals

and refrain from ‘when necessary’ ‘as needed’ or ‘PRN’ prescriptions; ●● By the appropriate route, preferable oral or

noninvasive routes; ●● By the child, taking the individual child into

account. The 2012 WHO guidelines [9] noted there was insufficient evidence to recommend any alternative opioid apart from morphine as the opioid of

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Pediatric pain management in palliative care  choice, and utilization of other opioids should be guided by consideration of safety, availability, cost and suitability. However, in clinical practice there is a large body of pediatric clinical experience regarding excellent safety and efficacy with the use of other mu-agonist opioids, namely, fentanyl, oxycodone, hydromorphone, diamoprhine (in UK only) and methadone. Oral administration of opioids is the recommended route and the guidelines give clear direction as to the dosages of the different medications, including adjuvants, for the management of persisting pain [9] . The WHO two-step approach is an effective strategy for the pharmacological management of persisting pain in children with medical illness, but does not mean that all the problems have been solved. For example, we are not sure concerning the use of tricyclic antidepressants and selective serotonin reuptake inhibitors as adjuvant medicines in the treatment of neuropathic pain in children, about use of any anticonvulsant as an adjuvant in the management of neuropathic pain, regarding the benefits and risks of ketamine as an adjuvant to opioids for neuropathic pain - regarding the benefits and risks of the systemic use of local anesthetics for persisting neuropathic pain, about the use of benzodiazepines and/or baclofen as an adjuvant in the management of pain in children with muscle spasm and spasticity [9] . ●●New drugs, new delivery systems & new

ways to use old drugs

The study of pharmacological management of pediatric pain has always been a difficult specialty. The complexity of pharmacodynamics and pharmacokinetics in children from neonate’s to young adults, as well as the costs and ethical issues of research has limited good evidence for the use of many drugs. Historically most drug use and dosages were extrapolated from adult palliative medicine and dosages altered on basis of weight or best guess. Over the last 5 to 10 years a great deal of research has led to improving qualities of published papers within this field. Pediatric palliative pain control has now reached the stage where it can start to teach adult palliative care a few tricks particularly around delivery systems. However it should be noted that many of the drugs discussed remain unlicensed for use either in children, or in children in the age groups that we use the analgesic drugs in, or in the delivery systems that we have used.

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The move to the two-step ladder [9] was primarily due to codeine being an inactive prodrug: Codeine’s ability to provide effective analgesia through its active metabolite morphine via the cytochrome P450 2D6 (CYP2D6) is limited both in ‘poor’ as well as ‘intermediate’ metabolizers in more than one-third of patients. Unfortunately there are substantial inter-individual and inter-ethnic differences in the conversion rates of codeine leading to uncertainty in its effectiveness particularly in children [9,24] . Recent concerns about codeine’s association with severe side effects in children, including death, led the US FDA to issue a warning about the use of codeine in children post tonsillectomy [27–30] . This has led to great difficulties, as the current recommendation is to use low-dose morphine. In many countries around the world morphine is very difficult to obtain and where it is available many parents are anxious at starting the child on what they see as a ‘painkiller’ that is used at end of life. Tramadol, although not recommended by the 2012 WHO guidelines [9] is extensively used around the world particularly where morphine is not available, often with a good analgesic efficacy and safety profile. Tramadol is a multi-mechanisms analgesic: (1) It is a centrally acting mu-opioid analgesic structurally related to morphine having two enantiomers, active metabolites and is rapidly and almost completely orally absorbed, as well as (2) a serotonin reuptake inhibitor. Studies examining efficacy and safety of this medication have been conducted worldwide, and results support its use in children  [31] . It comes in many forms and delivery Pain persisting or increasing

Pain decreasing

Strong-opioid ± non-opioid ± adjuvants

Non-opioid ± adjuvants

Step 2 Severe pain

Step 1 Mild pain

The WHO 2-step Analgesic Ladder

[Non-opioids = acetaminophen (paracetamol); ibuprofen]

Figure 1. Two-step ladder (nonopioids = acetaminophen [paracetamol]; ibuprofen). Data taken from [20].

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Review  Downing, Jassal, Mathews, Brits & Friedrichsdorf systems and has an analgesic potency of 10% to that of morphine. Data suggests that tramadol administration may result in fewer side effects than with opioid agonists, and tramadol appears safer than codeine when it comes to risk of respiratory depression. One study examining statewide poison control center data [32] reported no respiratory depression in children under 6 years of age who ingested 10/mg/kg or less (up to 5–10 times the recommended dose), however two out of 87 (2%) adults in the sample did experience respiratory depression. Over the last 5 to 10 years there has been a significant increase in interest in developing new delivery systems for drugs. This is evidenced through the increasing number of drugs that can be given through subcutaneous syringe drivers, intranasal, buccal/sublingual and transdermal routes. Subcutaneous syringe drivers that allow drug administration over 24 h are particularly useful towards the end of life or when there is difficulty in giving medication orally. They have become mainstay treatment within the UK and are being increasingly deployed in other countries around the world. Morphine, hydromorphone, fentanyl, diamorphine (not available outside UK) methadone and oxycodone can all be given via this route for nociceptive pain, as well as methadone and ketamine for neuropathic pain [33–35] . Drugs such as hydromorphone, diamorphine, fentanyl and alfentanil have been used intranasally for the management of acute pain in PICU and A&E for many years [36,37] . More recently they have been used in the palliative care setting for management of incidental or breakthrough pain. A drawback is around the irritation they may cause to nasal passages (which does not seem to occur with fentanyl) and the fact that some children may refuse to have more than one or two dosages this way because of the discomfort they may cause. The intranasal route however is fast acting and effective. The same three drugs can also be used by the buccal or sublingual route [36] . Fentanyl and hydromorphone (and diamorphine in UK) are particularly effective in that high dosages, can be mixed in small volumes of water, it is easily prepared, well absorbed through this vehicle route, acts rapidly, is very cheap and is palatable. It can be used in all age groups including neonates. The use of Alfentanil has very much been within PICU and with the advent of buccal diamorphine its role is limited. Although morphine, due to low

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liphophilicity, should be absorbed poorly sublingually, in fact there is good experience in a large number of infants and children providing effective symptom management of pain and/ or dyspnea in large programs with this route of administration. Both fentanyl and buprenorphine are available as transdermal patches [36] . Understanding of the dose equivalency to morphine and the rate of action is required by the physician instigating treatment particularly when doing opioid rotation [9,17,25] . The adult palliative world has led the way on the use of new drugs used for pain control. A number of these drugs have been used by PPC specialists in managing difficult pain. Methadone is a particularly good drug in terms of its actions on various receptors involved with pain [9,17,25,38] . However, due to its long half-life and complex conversion it is a somewhat difficult drug to initiate and titrate. As such it should only be used by specialists within the field. A review on the management of neuropathic pain in children with cancer identified that a combination of integrative, rehabilitative and supportive therapies with pharmacotherapy (e.g., NSAIDs, opioids, low-dose tricyclics, low-dose ketamine, alpha-agonists and gabapentinoids) are a useful treatment strategy [33] . However the management of neuropathic pain in children continues to be a challenge, and there remains a lack of evidence in this area. Low-dose ketamine might be a particularly effective drug for neuropathic pain [35,39] . It can be given by the oral or sublingual route. Its initial difficulties in terms of bitter taste have been improved by special formulation. It can also be administered subcutaneously or intravenously. It can however have potentially disturbing sideeffects such as agitation and hallucinations, especially in higher ‘anesthetic’ dosing. Gabapentin [17] and pregabalin [40] are now being used in most pediatric palliative specialist units for the management of neuropathic pain and visceral hyperalgesia. They have helped to revolutionize the management of difficult pains and pain syndromes. Gabapentin is a particularly inexpensive and effective drug to use. It does require a slow titration and so can take a period of time before its benefits become noticeable. Children particularly may have noticeable sedative effects from it if started on too high a starting dose, however these settle down with time. Pregabalin is a more expensive but also effective

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Pediatric pain management in palliative care  drug, which will often work when gabapentin in itself has failed (and the other way around). Alpha-agonist such as clonidine and especially dexmedetomidine appears to have excellent synergistic analgesic effects with opioids and may lessen opioid withdrawal symptoms [41] . Improving pain control around the world ”We have no pethidine [meperidine], no DF-118 (dihydrocodeine) and no morphine. We have children here with advanced HIV; some are in severe pain. The pain management for children with advanced HIV is not enough.”Nurse, Bondo District Hospital, Kenya (Human Rights Watch 2011 [42]). Pain in children is a public health concern of major significance in most parts of the world. Although the means and knowledge to relieve pain exist, children’s pain is often not recognized, is ignored or even denied [9,18] . Essential pain-relieving drugs continue to be so poorly available in most of the world that the WHO estimates that each year tens of millions of people suffer untreated moderate to severe pain [42] . Fourteen countries reported no consumption of opioid pain medicines between 2006 and 2008, meaning that there are no medicines to treat moderate to severe pain available through legitimate medical channels in those countries. Thirteen other countries do not consume enough opioids to treat even one percent of their terminal cancer and HIV/AIDS patients [42] . Two studies in Africa have looked at the availability of essential medications, such as analgesics, in 12 sub-Saharan countries [43] and then in health facilities in Kenya and Uganda [44] . Less than half of the facilities surveyed across the region were prescribing opioids, and challenges existed in terms of supply and skilled professionals to prescribe [43] . Out of 120 health facilities in East Africa, only 73% had nonopioid analgesics, and 7% morphine, with availability being better in hospitals than in health centers [44] . Thus demonstrating a clear challenge to pain management in children. Availability is not only a challenge in subSaharan Africa, but also in Asia, the Middle East, North Africa, Eastern Europe and Central America. Some of the world’s most populous countries have very poor availability of opioids for pain relief. Multiple barriers to palliative care are present. Palliative care is a public health issue, and the public health model for palliative care [45] states the need for policy,

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drug availability, education and implementation (with the latter addition of research as a foundation measure) [46] . Only 11 of the countries surveyed by Human Rights Watch have a national palliative care policy, despite WHO’s recommendation that countries put these in place. Most of the countries surveyed have inadequate opportunities for medical education in pain management or palliative care and in four of the countries – Cameroon, Ethiopia, Jordan and Tanzania – no such education is available at all. Survey findings also showed a large gap between availability of morphine in Western and Eastern Europe. Availability was best in France, Germany and the United Kingdom, with oral and injectable morphine available in most or all hospitals and pharmacies [42] . Canada and the USA have the highest opioid consumption per capita in the world. In 2010, the International Narcotics Control Board estimated that the levels of consumption of opioid analgesics were ‘inadequate’ in 21 countries and ‘very inadequate’ in more than 100 countries [47] . Poor availability of essential palliative care medicines offers a formidable barrier to proper pain management with 80% of the world’s population lacking adequate access. This includes the failure to put in place functioning drug supply systems, existence of unnecessarily restrictive drug control regulations and practices, fear among healthcare workers of prescribing opioid medications and the unnecessarily high cost of pain medications. Because of their potential for abuse, morphine and all other strong pain medicines are regulated under the Single Convention on Narcotic Drugs and national drug-control laws and regulations. This means that their manufacture, import and export, distribution, prescription and dispensation can only occur with government authorization. Once medications are available, it is important that they are accessible to the child in pain. Limitations on who can prescribe may exist, and those able to prescribe may be reluctant to, and pharmacists may also be concerned regarding the use of opioids in children. It is important for pharmacists to understand the issues that prevent children from receiving adequate pain control, e.g., misconceptions, fear of opioids, etc. [20] , as well as having a clear understanding of the management of pain in children, and the WHO guidelines – hence a document specifically for pharmacists has been developed as part of the package of materials on the new

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Review  Downing, Jassal, Mathews, Brits & Friedrichsdorf guidelines [48] . A recent review into the safety of prescribing opioids in pediatrics [49] sets out the issues involved, reviewing oral and intravenous administration of opioids, adverse effects and expert opinion, concluding that opioids can be safely used in children. The recent resolution on palliative care adopted by the World Health Assembly [50] affirms the need for access to essential medicines, including opioids. Member states are urged to ensure that they have ‘a medicines policy that will ensure the availability of essential medicines for the management of symptoms, including pain and psychological distress, and, in particular, opioid analgesics for relief of pain and respiratory distress.’ [50p19] Thus it is hoped that through the implementation of this resolution, progress will be made to ensure access to the medications needed for pain control in children. Integrative (nonpharmacological) pain management in PPC Whilst the WHO guidelines [9] focus on pharmacological management, integrative (nonpharmacological) pain management plays an ‘integrative’ integral part in PPC pain management, and the importance of providing multimodal analgesia and integrating nonpharmacological pain modalities is well documented in recent literature [51–55] . In the advanced management of pain in children with serious conditions in order to provide excellent analgesia without oversedation, it may be necessary to combine nonopioids, opioids, adjuvant analgesia, anesthetic or neurosurgical interventions with rehabilitative and especially integrative therapies. State of the art pain management in the 21st century demands that pharmacological management is no longer the sole approach to the management of a child’s pain and suffering [18,33,55] . Integrative therapies, used on their own or together with pharmacology, include cognitive behavioral techniques (such as guided imagery, hypnosis, abdominal breathing, distraction) and physical methods (such as cuddle/hug, massage, Transcutaneous Electrical Nerve Stimulation [TENS], comfort positioning, heat, cold, aromatherapy). Comprehensive pain control for children with life-limiting illness requires tailoring to the needs of the individual child and integrating methods of pain management [18,33] . Mind-body interventions constitute a major portion of the overall use of Complementary Alternative Medicine by the public [56] .

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Mind-body medicine focuses on intervention strategies that integrate mind processes with body function and experience in order to promote health. For children and teens, these include relaxation, hypnosis, imagery, meditation, yoga, biofeedback, cognitive-behavioral therapies, group support, autogenic training and spiritual practices [57] . Active distraction techniques, such as imagery, appear to modulate endorphin release in the midbrain, including the periaqueductal grey, and thereby increase activity of descending inhibiting pathways thereby decreasing nociception from the dorsal horn resulting in gate pain modulation during distraction [58] . As a result, many pediatric pain and palliative care services worldwide, such as the Children’s Hospitals and Clinics and Minnesota (USA), have integrated safe Complementary Alternative Medicine methods in their daily clinic care. Examples of such methods include [55] : ●● Imagery. A gentle, nonintrusive, child-cen-

tered, therapeutic modality, which can provide a meaningful alternate experience when the present reality is fraught with pain, fear, fatigue or physical tension. Imagery can be used in many ways, e.g., focusing directly on the distressing pain symptom and engaging with it so that it begins to change, or creating a favorite or familiar image that is a more pleasant alternative to the distressing symptom. Imagery is a precursor to hypnosis, and often used as an induction to hypnotic trance in which change can more rapidly occur. When used for pain control, imagery works synergistically with analgesics to reduce pain and discomfort [59,60] ; ●● Self-hypnosis. Hypnosis involves the cultiva-

tion of an altered state of awareness, leading to heightened suggestibility that allows for changes in a child’s perception and experience, bypassing conscious effort. In hypnosis the clinician enters the child’s world, engaging the child’s imagination as the agent of change and creating alternate experiences to promote therapeutic change. In trance, the child addresses distressing symptoms utilizing suggestions by the clinician for altering sensations, perceptions and increasing comfort [61–63] ; ●● Biofeedback. A self-regulatory skill that uses

electronic or electromechanical equipment to

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Pediatric pain management in palliative care  measure and then return information about physiologic functions, which the child uses to gain control over these responses in a desired direction. The functions include, heartbeat, blood pressure and muscle tension. The feedback is provided in auditory, visual and multimedia game formats that appeal to children [64,65] ; ●● Yoga. A 5000‐year-old practice from Ayurve-

dic medicine that combines breathing exercises, physical postures and meditation. Experience suggests that yoga can be of benefit during palliation if the child or teen is already familiar with the practice, has used diaphragmatic breathing, or has favorite postures (asanas) that ease pain, reduce anxiety or discomfort, such as the ‘child’s pose’ or ‘cat stretch’ [66,67] ; ●● Music. Music has been used for centuries to

soothe distress and is thought to help reorganize and reregulate the nervous system, improving mood [68,69] ; ●● Aromatherapy. Hundreds of receptor cells

have been identified in the nasal passages which relay smell to the brain. Essential oils are highly concentrated nonoily, fragrant substances extracted from plants by distillation, which evaporates readily. Aromatherapy is thought to work by promoting the release of neurotransmitters once the nasal receptor cells are stimulated by these distilled fragrances [70] ; ●● Massage. For example, pressing, rubbing and

moving muscles and other soft body tissues primarily using the hands and fingers. Massage therapy in a PPC setting can have significantly unique demands, and therefore the term massage can be confusing. Hence the terminology is sometimes changed to ‘Integrative Touch’ or ‘Compassionate Touch’ [71,72] . In addition, psychological treatments such as Cognitive-behavioral therapy or Acceptance and Commitment therapy can significantly reduce pain intensity reported by children and adolescents with chronic pain [73,74] . Cognitive-behavioral therapy increases prefrontal cortex gray matter in patients with chronic pain and is associated with reduced pain catastrophizing [75] .

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Education & research Whilst the 2012 WHO guidelines [9] and the literature are focused mainly on the clinical aspects of the management of pain in PPC, there is a need for education on the management of pain in children, as emphasized within the guidelines. The 2012 WHO guidelines recognize the need for training and education on ‘the standardized management of persisting pain in children with medical illnesses and in the handling of the necessary medicines, including opioid analgesics’ [9p59]. Indeed, several of the barriers to managing pain in children still mentioned in the literature include that of a deficit in knowledge by health professionals of how to assess and manage pain in children, and the use of opioids such as morphine [11,18–20] . Health professionals therefore need to be educated about the options for managing pain, including different medications, pharmacological and integrative approaches, plus information about regulations governing the prescribing of controlled medicines such as morphine [76] . However, medical undergraduates as well as post graduate students specializing in pediatrics, family medicine, oncology or anesthesia receive little or no exposure to palliative care and pain management in their training, despite the fact that WHO has called on countries to ensure adequate instruction of health workers on pain management. This could be the first step to ensuring that children in need of palliative care get access to proper and effective pain management. A recent survey by the ICPCN [77] of 80 participants from 32 countries highlighted the need for education and training and revealed gaps in knowledge of the WHO guidelines and pain management in general as one of the main barriers for pain control in children. There are an increasing number of courses and curricula available on pediatric PPC internationally, including those specifically on pain assessment and management [78,79] , taught programs, blended approaches and e-learning, e.g., EPEC (http://epec.net/epec_pediatrics.php) and the ICPCN programs (www.elearnicpcn. org). Education programs should involve not only the acquisition of knowledge, the development of skills, but also the cultivation of attitudes for PPC, self-awareness and reflective practice [80,81] . A recent report of the European Association of Palliative Care (EAPC) Children’s Palliative Care Education Taskforce looking at core competencies for education in PPC [82,83] identified key competencies on pain assessment

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Review  Downing, Jassal, Mathews, Brits & Friedrichsdorf and management for ‘General PPC’ education programs, which are then developed further at the specialist level (Table 1) . Resources are available on the WHO guidelines [9] to aid education. Alongside the guidelines themselves brochures have been developed for physicians and nurses, pharmacists, policy makers and medicines regulatory authorities, hospital managers and health insurance managers, a dosing card, pain scales and wall charts. All documents are downloadable free from the WHO website and a training module based on the guidelines has been made available by the ICPCN (www.elearnicpcn). With the increase in availability of education programs, the impact of such programs is now being reported in the literature, e.g., in Italy [84] and the USA [85] , along with the identification of professionals’ knowledge on palliative care so that courses can be developed according to need, for example, in Uganda [86] and in Jordan [87] . The need for more research on pain in PPC is a key recommendation from the WHO guidelines [9,11] . There is little evidence in many of the different aspects of the management of pain in children (both pharmacological and integrative), thus a research agenda was formulated in 2010 whilst the available evidence was being reviewed for the guidelines. Research topics were put into four priority groups, specific to the pharmacological management of persisting pain in children, and covered four main areas: clinical studies needed on acetaminophen (paracetamol), NSAIDs and opioid analgesics, clinical studies on adjuvant medicines for neuropathic pain, pharmacokinetics and pain assessment tools [9,11] . Top priorities include assessment of the two-step analgesic ladder, research on alternative strong opioids, on intermediate potency opioid analgesics such as tramadol, and long-term safety data concerning first step medicines (ibuprofen and acetaminophen [paracetamol]) [9p129].

Strengthening the evidence base for children’s palliative care, and pain management specifically, is a priority in order to strengthen the guidelines, and ensure that children throughout the world are getting access to the best possible pain management, in order to reduce suffering and improve quality of life. Thus there is an urgent need for a collaborative effort involving the clinical community and research institutions in multicenter studies around the world [11] . Conclusion In summary, the publication of the 2012 WHO Guidelines [9] has been a key development in the last five years for the management of pain in PPC. Alongside these guidelines, studies into both pharmacological and integrative management continue to be published, and the evidence base continues to increase. However, whilst significant advances have been made in the understanding of pain management in PPC, it is clear that significant gaps still exist, e.g., in terms of the evidence base, the ongoing need for education and training, access to essential medications, etc. Whilst the guidelines for managing persisting pain in children with medical illnesses are a step forward, they do highlight the gaps in our current knowledge of pain assessment and management in PPC. Thus the optimal way of managing persistent pain in children with medical illnesses is still to be agreed and requires both multidisciplinary and international collaboration [10] . Future perspective It is anticipated that some of these gaps in terms of the evidence base and education, will be narrowed over the coming years, with the call for more research to develop the evidence base, the expansion of education and training programs on pain management in PPC, and it is hoped that the WHO resolution will

Table 1. Competencies on pain as stated for general pediatric palliative care education programs [74p21]. Domain

Competencies

Physical care    

Acquire knowledge of common physical symptoms in pediatric palliative care Recognize common misconceptions regarding pain in children and explain how these impede optimal pain management Identify and utilize suitable assessment tools

       

Demonstrate effective documentation of pain and symptoms Demonstrate safe and effective use of widely use of medications in pediatric palliative care Demonstrate effective use of analgesic ladders in managing pain and of adjuvant drugs in symptom control Identify nonpharmacological approaches to symptom management

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Pediatric pain management in palliative care  encourage member states into action such that they implement the recommendations in the resolution and break down barriers to pain control in children around the world, thus bringing an end to unnecessary suffering [88] . Whilst the list of research priorities has been developed, it is encouraging to note that many of the proposed items are already being researched with results due out in the coming years [10] . It is important to note evidence in PPC may be derived from methods other than randomized controlled trials in some situations, and that randomized controlled trials References Papers of particular interest, published within the period of review, have been highlighted as: • of interest; •• of considerable interest 1

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•• An important document for managing pain in pediatric palliative care setting out the

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from adults are not necessarily appropriate for the pediatric population. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. guidelines and rationale as to how we do this.

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