PALLIATIVE CARE SECTION

Cancer Pain: Part 2: Physical, Interventionaland Complimentary Therapies; Management inthe Community; Acute, Treatment-Related andComplex Cancer Pain: A Perspective from theBritish Pain Society Endorsed by the UKAssociation of Palliative Medicine and theRoyal College of General Practitionerspme_841 872..896

Jon Raphael, MB, ChB, MSc, FRCA, MD, FFPMRCA,*Joan Hester, MB, BS, FRCA, MSc, FFPMRCA,†Sam Ahmedzai, BSc, MB, ChB, FRCP,‡‡

Janette Barrie, RN, MSc,§§ Paul Farqhuar-Smith,MB, BChir, FRCA, PhD, FFPMRCA,‡ John Williams,MB, BS, FRCA, FFPMRCA,‡ Catherine Urch, BM,MRCP, PhD,§ Michael I. Bennett, MB, ChB, MD,FRCP, FFPMRCA,¶¶ Karen Robb, BSc, PhD, MCSP,¶Brian Simpson, MA, MB, BChir, MD, FRCS,***Max Pittler, MD, PhD,†††† Barbara Wider, MA,†††

Charlie Ewer-Smith, DipCOT, CMS,‡‡‡

James DeCourcy, MBBS, FRCA,****Ann Young, MB ChB,**** Christina Liossi, BA, MSc,MPhil, DPsych,§§§ Renee McCullough, BM, BS,MRCP, DIP, PAL, MED,** Dilini Rajapakse, MBBS,MSc, MRCPCH,** Martin Johnson, MB, ChB,MRCGP,†† Rui Duarte, BSc,* andElizabeth Sparkes, BSc¶¶¶

*Faculty of Health, Birmingham City University,Birmingham, UK;

†Pain Management, Kings College Hospital, London,UK;

‡Anaesthetics, Royal Marsden Hospital, London, UK;

§Palliative Medicine, St. Marys Hospital, London, UK;

¶Physiotherapy, St. Bartholemews Hospital, London,UK;

**Paediatric Palliative Medicine, Great Ormand StreetHospital, London, UK;

††General Practice, Royal College of GeneralPractitioners, London, UK;

‡‡Palliative Medicine, University of Sheffield, Sheffield,UK;

§§Long Term Conditions, Lanarkshire Health,Scotland;

¶¶End of Life Observatory, Lancaster University,Lancaster, UK;

***Neurosurgery, University Hospital Wales, Cardiff;

†††Complimentary Therapy, Peninsula Medical School,Exeter, UK;

‡‡‡Occupational Therapy, University Bristol Hospital,Bristol, UK;

§§§Psychology, Southampton University, Southampton,UK;

¶¶¶Psychology, Coventry University, Coventry, UK;

****Pain Management, Gloucestershire Hospital,Gloucester, UK;

††††Science, German Institute for Quality andEfficiency in Health Care, Cologne, Germany

Reprint requests to: Jon Raphael, MSc, MD,Birmingham City University, Faculty of Health,Graduate School, Ravensbury House, WestbourneRoad, Westbourne Campus, Edgbaston, BirminghamB15 3TN, UK. Tel: +44(0)1384 244809; Fax:+44(0)1384 244025; E-mail: jon.raphael@bcu.ac.uk.

Pain Medicine 2010; 11: 872–896Wiley Periodicals, Inc.

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Abstract

Objective. This discussion document about themanagement of cancer pain is written from the painspecialists’ perspective in order to provoke thoughtand interest in a multimodal approach to the manage-ment of cancer pain, not just towards the end of life,but pain at diagnosis, as a consequence of cancertherapies, and in cancer survivors. It relates thescience of pain to the clinical setting and explains therole of psychological, physical, interventional andcomplementary therapies in cancer pain.

Methods. This document has been produced by aconsensus group of relevant healthcare profession-als in the United Kingdom and patients’ representa-tives making reference to the current body ofevidence relating to cancer pain. In the second oftwo parts, physical, invasive and complementarycancer pain therapies; treatment in the community;acute, treatment-related and complex cancer painare considered.

Conclusions. It is recognized that the World HealthOrganization (WHO) analgesic ladder, whilst provid-ing relief of cancer pain towards the end of life formany sufferers world-wide, may have limitationsin the context of longer survival and increasingdisease complexity. To complement this, it is sug-gested that a more comprehensive model of manag-ing cancer pain is needed that is mechanism-basedand multimodal, using combination therapies inclu-ding interventions where appropriate, tailored to theneeds of an individual, with the aim to optimize painrelief with minimization of adverse effects.

Key Words. Cancer Pain; Palliative Treatment

Preface

This discussion document, which can be more fullyaccessed at www.britishpainsociety.org/book_cancer_pain.pdf, about the management of cancer pain is writtenfrom the pain specialists’ perspective in order to provokethought and interest in a multimodal approach to themanagement of cancer pain, not just toward the end oflife, but pain at diagnosis, as a consequence of cancertherapies, and in cancer survivors. It relates the science ofpain to the clinical setting and explains the role of psycho-logical, physical, interventional and complementary thera-pies in cancer pain.

It is directed at physicians and other health care profes-sionals who treat pain from cancer at any stage of thedisease and it is hoped that it will raise awareness of thetypes of therapies that may be appropriate, heightenappreciation of the role of the pain specialist in cancer painmanagement, and lead to dialogue and liaison betweenoncology, specialist pain and palliative care professionals.

This document is accompanied by information for patientsto help them and their carers understand the availabletechniques and to support treatment choices.

Methods

This document has been produced by a consensus groupof relevant health care professionals and patients’ repre-sentatives making reference to the current body of evi-dence relating to cancer pain.

Executive Summary

• It is recognized that the World Health Organisation(WHO) analgesic ladder, while providing relief of cancerpain toward the end of life for many sufferers world-wide, may have limitations in the context of longer sur-vival and increasing disease complexity. To complementthis, it is suggested that a more comprehensive modelof managing cancer pain is needed that is mechanism-based and multimodal, using combination therapiesincluding interventions where appropriate, tailored tothe needs of an individual, with the aim to optimize painrelief with minimization of adverse effects.

• The neurophysiology of cancer pain is complex; itinvolves inflammatory, neuropathic, ischemic, and com-pression mechanisms at multiple sites. Knowledge ofthese mechanisms and the ability to decide if a pain isnociceptive, neuropathic, visceral or a combination of allthree will lead to best practice in pain management.

• People with cancer can report the presence of severaldifferent anatomical sites of pain that may be caused bythe cancer, treatment of cancer, general debility or con-current disorders. Accurate and meaningful assess-ment and reassessment of pain is essential andoptimizes pain relief. History, examination, psychosocialassessment and accurate record keeping should beroutine, with pain and quality of life measurement toolsused where appropriate.

• Radiotherapy, chemotherapy, hormones, bisphospho-nates and surgery are all used to treat and palliatecancers. Combining these treatments with pharmaco-logical and nonpharmacological methods of paincontrol can optimize pain relief, but limitations of thesetreatments have also to be acknowledged.

• Opioids remain the mainstay of cancer pain manage-ment, but the long-term consequences of tolerance,dependency, hyperalgesia and suppression of thehypothalamic/pituitary axis should be acknowledgedand managed in both noncancer and cancer pain, aswell as the well known side-effects such as constipation.NSAIDs, anti-epileptic drugs, tricyclic antidepressants,NMDA antagonists, sodium channel blockers, topicalagents and the neuraxial route of drug administration allhave a place in the management of complex cancer pain.

• Psychological distress increases with intensity of cancerpain. Cancer pain is often under reported and under-treated for a variety of complex reasons partly due to anumber of beliefs held by patients, families and healthcare professionals. There is evidence that cognitivebehavioral techniques that address catastrophizing and

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promote self efficacy lead to improved pain manage-ment. Group format pain management programs couldcontribute to care of cancer survivors with persistentpain.

• Physiotherapists (PTs) and occupational therapists(OTs) have an important role in the management ofcancer pain and have specific skills that enable them tobe patient-focused and holistic. Therapists utilize strat-egies that aim to improve patient functioning and qualityof life, but the challenge remains to practice in anevidence-based way and more research is needed inthis field.

• Patient selection for an interventional procedurerequires knowledge of the disease process, the prog-nosis, the expectations of patient and family, carefulassessment and discussion with the referring physi-cians. There is good evidence for the effectiveness ofcoeliac plexus neurolysis and intrathecal drug delivery.Within the limitations of running randomized controlledtrials (RCTs) for interventional procedures in patientswith limited life expectancy and severe pain, there is abody of evidence of data over many years that supportsan important role for some procedures (e.g., cordo-tomy). Safety, aftercare and management of possiblecomplications have to be considered in the decisionmaking process. Where applied appropriately and care-fully at the right time, these procedures can contributeenhanced pain relief, reduction of medication use andmarkedly improved quality of life.

• There is a weak evidence base for the effectiveness ofcomplementary therapies in terms of pain control, butthey may improve well being. Safety issues are also aconsideration.

• Patients with cancer pain spend most of their time in thecommunity until the last month of life. Older patientsand those in care homes may particularly have under-treated pain. Primary care teams supported by palliativecare teams are best placed to initiate and managecancer pain therapy, but education of patients, carersand health care professionals is essential to improveoutcomes.

• Surgery, chemotherapy and radiotherapy are cancertreatments that can cause persistent pain in cancersurvivors, up to 50% of whom may experience persis-tent pain that adversely affects quality of life. Awarenessof this problem may lead to preventative strategies, but,at the moment, treatment is symptom based and ofteninadequate.

• Management of acute pain, especially postoperativepain, in patients on high dose opioids is a challengethat requires in-depth knowledge of pharmacoki-netics and formulation of a careful management plan toavoid withdrawal symptoms and inadequate painmanagement.

• Chronic pain after cancer surgery may occur in up to50% of patients. Risk factors for the development ofchronic pain after breast cancer surgery include: youngage, chemo and radiotherapy, poor postoperative paincontrol and certain surgical factors. Radiotherapyinduced neuropathic pain has become less prevalentbut can cause longstanding pain and disability.

• Patient education is an effective strategy to reduce painintensity.

• Cancer pain is often very complex but the most intrac-table pain is often neuropathic in origin, arising fromtumor invasion of the meninges, spinal cord and dura,nerve roots, plexuses and peripheral nerves. Multimodaltherapies are necessary.

• The management of cancer pain can and should beimproved by better collaboration between the disci-plines of oncology, pain medicine and palliative medi-cine. This must start in the training programmes ofdoctors, but also in established teams in terms offunding, time for joint working, and education of allhealth care professionals involved with the treatment ofcancer pain.

• The principles of pain management and palliative care inadult practice are relevant to pediatrics, but the adultmodel cannot be applied directly to children.

Part 2 of 2: Physical, Invasive and ComplementaryCancer Pain Therapies; Treatment in theCommunity; Acute, Treatment-Related andComplex Cancer Pain

Physical Therapies in Cancer Pain

Summary

PTs and OT) have an important role in the management ofcancer pain and have specific skills which enable them tobe patient-focused and holistic. Therapists utilize strate-gies that aim to improve patient functioning and quality oflife but the challenge remains to practice in an evidence-based way. More research is needed in this field.

Introduction

PT and OT play an important role in the management ofpatients with cancer pain and may encounter thesepatients at various stages in the “cancer journey.” Reha-bilitation of cancer patients is gaining increasing recogni-tion and is now considered an essential component in thedelivery of care [1].

The main aims of therapy are to relieve pain (whereverpossible) and to improve function and quality of life usingtreatments based on the best available evidence. Manage-ment should be patient-centered, collaborative and restor-ative and involve family and carers to ensure a coordinatedapproach to treatment planning and goal-setting. Thepatient’s engagement in the therapy partnership is vital.

Early referral to therapies is important not only with thepalliative care patients, but also with others, to preventchronicity and help anticipate future problems. Within-patients, early referral should result in better dischargeplanning that may stop bed blocking and help patientsreturn to their preferred place of care.

Much can be learned from therapists who work with mus-culoskeletal pain and there is a plethora of literature exam-

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ining the role of physiotherapy and occupational therapyfor patients with benign pain. Therapists working withcancer patients may find some of these messages helpfulbut must recognize that the majority of this work hasfocused on a noncancer population.

Assessment

Impact of Cancer-Related Pain

Pain can reduce strength, vitality, activity tolerance andmobility [2,3]. Cancer patients with pain report significantlylower levels of performance status than those without pain[4,5] demonstrated that pain due to cancer was associ-ated with higher levels of perceived disability and a lowerdegree of activity. Pain may affect a person’s ability to carefor themselves, to work or to participate in fulfilling activi-ties. The experience of cancer pain may also result indisruption to family and carers’ quality of life [6].

A common response to pain is the development of “painbehaviors.” This includes maladaptive behaviors such asguarding the painful area, pain watching (hyper-vigilance),developing an overly sedentary lifestyle and avoidingactivities. This inactivity can result in deconditioning,increased muscular tension and increased attention topain.

Responses to Cancer-Related Pain

It is essential to explore the meaning of pain to the patientand to those closest to them. An individual’s cultural back-ground, spiritual, religious and philosophical beliefs allimpact upon perception and response to cancer pain.

Thoughts and emotional responses can contribute to theintensity of the pain experience [7]. Anxiety, depression,fear of the future, hopelessness, negative perceptions ofpersonal and social competence, decreased socialactivity/social support and lack of control over pain may allbe important [8].

Principles of Assessment

Therapy assessments must include subjective and objec-tive evaluation and must utilize all available informationfrom medical notes, other members of the MDT andpatients and carers themselves. All relevant comorbiditiesneed to be considered. Assessment is rarely possible overone interaction; it is an information gathering exercise andis a continual process which guides initial and ongoingtreatment. Optimal timing of pharmaceutical managementis often required to enable patients to participate fully inassessment.

Physiotherapy Assessment

This will require detailed examination of physical factors(e.g., joint range of movement, muscle power, posturalchanges); with recognition of and appropriate manage-ment of psychological comorbidities (e.g., anxiety or

depression). Assessment will focus on a patient’s func-tional ability (e.g., their ability to transfer or mobilize). Thereare three components of assessment that must be con-sidered in all patients: a description of the pain (includingsite, severity, irritability, nature); responses to the pain andthe impact of pain on the person’s life [9].

Therapists must be aware of the dangers of placing toomuch attention on correction of physical impairments atthe expense of function [10]. For many cancer patients(especially those with advanced disease) it will be moreimportant to complete a task than to focus on correctionof individual impairments.

Occupational Therapy Assessment

Occupational therapy assessment recognizes it is usualfor cancer patients to identify and focus on those tasksand occupational roles that they are no longer able tomanage or enjoy due to their pain. The OT will listen to thepatient’s narrative and begin to identify aggravating, reliev-ing factors; the beliefs held regarding pain; what the painmeans to the patient, those around them; how the patientis currently managing their activities in relation to theirpain.

The OT will identify which activities the individual needs todo, wants to do and is expected to do by others.

Evaluating Outcome

It is important to utilize reliable and valid outcome mea-sures as well as utilizing patient’s subjective feedback.Outcome measures for use in clinical practice must befeasible (i.e., practical, inexpensive and easy to use),provide extra clinical information and be responsive tochanges over time. A great variety of tools are now avail-able but there are no published guidelines for therapists toassist selection of measures.

Outcome Measures

Both visual analog scales and numerical ratings scales(NRSs) are commonly used in clinical practice. Previousresearch has suggested cutoff points for mild, moderateand severe pain on a NRS, with 0–4 mild, 5–6 moderate,7–10 severe. This is useful to consider when asses-sing whether improvements in pain report are clinicallysignificant.

Example: A drop in pain report from 9/10 to 7/10 may beless clinically significant than a drop from 7/10 to 5/10,although the incremental change is the same.

The brief pain inventory [12] is a useful clinical tool fortherapists as it reports both pain intensity and pain inter-ference using a NRS.

It is important that the patient remains at the center of thetreatment process. A measure that can be used to detectthe impact of therapy intervention on the patient’s self-

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perception of occupational performance is the CanadianOccupational Performance Measure [13]. It has also beendemonstrated to empower and actively encourage patientparticipation in therapy interventions.

Other tools that can be used include pain drawings (oftensimple body charts) or descriptive questionnaires such asthe McGill Pain Questionnaire [14].

Therapy Management

The ultimate aim is for the patient to achieve full functionalpotential and become autonomous in managing theimpact of pain on their daily life. There is currently a lack ofevidence for the use of therapy interventions for patientswith cancer-related pain and research is required in thisfield. Interventions can be classified as physical, psycho-social and lifestyle adjustment.

Physical Approaches

Some of these approaches are traditionally administeredby PTs (e.g., therapeutic exercise and transcutaneouselectrical nerve stimulation [TENS]) but other health carepractitioners (HCPs) may have sufficient skills in this area(e.g., OT, clinical nurse specialists). Graded activity forreturn to function is inextricably linked with therapeuticexercise but may traditionally be considered the domain ofthe OT. When utilizing these approaches, a certain amountof manual handling is required and therapists must payspecial attention to patient comfort and position at alltimes.

Therapeutic Exercise

The main goal of exercise is to address the problemsassociated with inactivity/immobility (specific or general)and fear of movement. The detrimental effects of immo-bilization are well documented and include musclewasting/weakness, joint stiffness, reduced motor control,mood changes, decreased self-efficacy, reduced copingcapacity and cardiovascular deconditioning. Exercise pro-grams must be tailored to the individual needs of thepatient and should start cautiously, build up gradually andbe within patients’ tolerance levels. There are now manyreviews of exercise in cancer patients, some of whichinclude guidance on specific precautions [15,16].

Graded and Purposeful Activity

Engagement in meaningful activities (which may includecraft, recreation or work) has been shown to assistpatients with cancer pain to improve their self-conceptand attain task mastery [17]. Appropriately prescribed andgraded activities, can be used to increase activity toler-ance, autonomy, social integration, self-esteem and com-petency, and decrease pain behaviors [18].

Postural Re-education

Postural re-education is appropriate in patients who havealtered posture or movement secondary to pain. It isimportant to attempt correction of such postural abnor-malities early in rehabilitation to avoid further dysfunctionalmovement patterns. Examples include breast cancerpatients who develop chronic postsurgical pain followingbreast cancer treatment and adopt protective posturesresulting in muscle spasm and muscle imbalances [19]. Inhead and neck cancer patients, there is growing evidencefor the use of Progressive Resistive Exercise training tomanage shoulder dysfunction and pain secondary tospinal accessory nerve damage. The importance of cor-recting posture and scapular stability prior to resistanceexercise has been documented [20].

Massage and Soft Tissue Mobilization

Soft tissue mobilization is widely practiced in the manage-ment of pain and includes techniques such as scarmobilization/massage, myofascial techniques and con-nective tissue massage. A wealth of information is avail-able on such approaches [21,22].

TENS

TENS is a noninvasive form of electrical stimulation thathas been used for many years to treat a wide range of painproblems. Although experts suggest that TENS has animportant role there are currently no formal guidelines onthe use of TENS in cancer patients. Only two RCTs evalu-ating TENS use in cancer-related pain have been identified[23,24] and the effectiveness of TENS remains inconclu-sive [25]. Yet some patients may find it beneficial.

Conventional TENS is the most common mode of deliveryused in practice and should be the first treatment option inmost situations. It is generally recommended to start withTENS electrodes in the painful area or an adjacent der-matome. The intensity should be “strong but comfortable”and patients can safely increase treatment time up toseveral hours as long as no side-effects occur and benefitcontinues.

Heat and Cold Therapy

Application of heat can be achieved from simpleapproaches (e.g., a hot bath to aid relaxation or more localapplications such as heated packs). Cold can be deliveredvia ice packs and home remedies can be devised (e.g.,using frozen peas, wrapped in a towel or protective fabricto prevent frost burn). All standard contraindications andprecautions must be followed and choice of treatment willdepend on pain presentation and the therapeutic effectsneeded.

Lifestyle Adjustment

Typically, it is the OT who addresses this aspect of man-agement although the PT can also be involved in some

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aspects (e.g., prescription of walking aids). Analysis ofactivity tolerance levels and education in skills can enablefunctional restoration without provoking painful episodes.Techniques such as pacing, planning, prioritizing, energymanagement, activity analysis, work simplification, timemanagement, compensatory techniques, ergonomic prin-ciples, and the reorganization of routines can be taught toprovide the patient with skills to restructure their lifestyle,thus minimizing painful episodes.

Analyzing, grading and adapting activities allows patientsto continue managing them within their ability, tolerancelevel and pain parameters [26,27]. The restructure of lif-estyle and routine, environmental adaptation, task simpli-fication, fatigue management, appropriate equipment andorthotic prescription and interventions regarding correctpositioning and pressure relief during activity facilitateindependence, conserve energy, minimize pain on exer-tion and enable valued activities to be continued.

Invasive Procedures in Cancer Pain

Summary

Patient selection for an interventional procedure requiresknowledge of the disease process, the prognosis, theexpectations of patient and family, careful assessment anddiscussion with the referring physicians. There is goodevidence for the effectiveness of coeliac plexus block andintrathecal drug delivery. Safety, aftercare and manage-ment of possible complications have to be considered inthe decision making process. Where applied appropriatelyand carefully at the right time, these procedures can con-tribute enhanced pain relief, reduction of medication useand markedly improved quality of life.

Introduction

This chapter focuses on the interventional proceduresconsidered the most effective. It deals with the pharma-cological blockade of neural tissue by targeted injectionor infusion, their destruction by chemical, physical or sur-gical methods and the fixation of vertebral compressionfractures.

For a few procedures (coeliac plexus ablation, intrathecalinfusions, see below) there is controlled trial evidence incancer populations. For most procedures there is lessrobust evidence of largely uncontrolled case series.

A pragmatic approach is required when deciding whetherto offer such therapies. The likely benefits and possiblerisks need to be considered and compared with those ofcontinuing with pharmacological management. Typically,interventional management of cancer pain does not sub-stitute for other modalities but can improve pain relief andallow for a reduction in systemic medications and theirside-effects.

Careful assessment of the pain should be undertaken byan interdisciplinary team usually including specialists in

pain, palliative care and nursing. The team might includeothers. Practical factors should be considered, suchasdischarge home, patient and family preferences.Complex situations will often require high level discussion.

It has been traditional to consider exhausting oral ortopical analgesia before considering invasive methods;however, this is not always in the patients best interests.Where there are unacceptable side-effects from opioids,such as drowsiness, then invasive methods may be pre-ferred or an implanted pump early in advanced cancer canallow for the maximum benefit to be obtained.

This chapter aims to bring information related to benefitsand adverse effects for interventional procedures com-monly used in cancer pain management.

Types of Interventional Procedures

These most typically involve interruption to or modificationof nerve conduction with the aim of diminishing pain froma target area. The nerves involved include those of theperipheral, autonomic and central nervous system.

The procedures may be considered as nondestructive ordestructive. In nondestructive procedures, nerve blockadeor modulation is achieved by the deposition of reversiblepharmacological agents. These may be provided by bolusinjection and most commonly involve local anestheticagents often supplemented by depot steroids. Alternativelycatheter placement allows for the continuous delivery ofagents. When placement is adjacent to peripheral or auto-nomic nerves similar agents are used. For catheter place-ment in the spinal canal with the aim of modulating neuronalactivity of the spinal cord, different agents are used. Theseare most commonly opioids often supplemented by localanesthetics and/or the alpha-2 adrenergic agonist, cloni-dine. More recently, the voltage gated calcium channelblocker, ziconotide has been introduced [28].

The destructive procedures involve the use of chemicalagents (alcohol 50–100% and phenol 6–10%), physicalmethods of heat (radiofrequency) and cold (cryoablation)and surgery.

Destructive procedures must only be provided by appro-priately trained personnel, and are best offered within amultidisciplinary framework of care recognizing the psy-chosocial components of pain experience. Failure to do sois likely to reduce the efficacy of such procedures.

Patients should be thoroughly informed about likelysensory deficits and possible complications. In mostcases, destructive procedures should first be simulatedwith local anesthetic to allow the patient to experience thesensory changes that may occur [29].

The patient should be closely followed as an inpatient forseveral days after the destructive procedure with closemonitoring and planned opioid reduction to avoid drowsi-

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ness and respiratory depression when the respiratorystimulation of pain is removed.

Peripheral Nerve Blockade

Peripheral nerve blocks have a limited role in cancer painmanagement. There is no controlled trial evidence butcase series describe pain relief for a short time with localanesthetic blockade of the regional nerve supply of atarget area. They may therefore be useful for perioperativepain, and other acute cancer pains such as pathologicalrib fracture (intercostal nerve blockade). This may beachieved by bolus injection of local anesthetic. It is oftensupplemented with depot steroid with the aim of providinglonger term relief but there is no evidence to support thisfor peripheral nerves [30]. Alternatively, catheter infusionsof local anesthetic adjacent to brachial plexus [31] or othernerves may prolong the pain relief [32,33].

Neurolytic blockade of peripheral nerves produces short-term relief, for example, intercostal neurolysis has amedian duration of 3 weeks [34]. Although this studyfound no incidences of neuritis, the survival time wasshort, and others have reported an incidence of neuritis of30% [35]. Neurolytic agents should be limited to thosewith short life expectancy.

Autonomic Nerve Blockade

It is known that the sympathetic nervous system carriespain afferents from the viscera and that blockade canreduce pain.

Coeliac Plexus Ablation

The coeliac plexus carries visceral afferents from severalabdominal organs including the pancreas, liver, biliarytract, renal pelvis, ureter, spleen, and bowel up to the firstpart of the transverse colon.

Injection of a neurolytic medication around the coeliacplexus has been most investigated for pancreatic cancerpain but has found a role for other upper gastrointestinalmalignancies such as gastric cancer, esophageal cancer,colorectal cancer, liver metastasis, gallbladder cancer andcholangiocarcinoma [36].

Access to the plexus is most commonly posterior withneedle placement in front of or posterior to the crura of thediaphragm [37], but other approaches are used such asanterior [38], endosopic [39] and transdiscal [40]. Imagingmost commonly involves fluoroscopy but alternatives usedinclude computerized tomography [41] and MRI [42]. Whilethere is no apparent difference in outcome between thesemethods, they do allow for access in certain individualswhere fibrous infiltration or tumor invasion may distort theanatomy affecting neurolytic spread [43,44] or may bevaluable when patients cannot lie on their front [45].

In a single-blind RCT of 100 patients with pancreaticcancer, neurolytic plexus ablation was compared with

pharmacological management together with sham proce-dure. Pain relief was better in the interventional group for 6weeks [46]. A meta-analysis [47] of five RCTs of coeliacplexus ablation, found significantly improved pain reliefwhen compared with pharmacological management orlocal blockade of the plexus for 8 weeks with reducedopioid consumption in the ablation group.

Up to 30% of patients experience hypotension after coeliacplexus block due to loss of sympathetic tone and splanch-nic vasodilatation [48]. This reaction usually manifests itselfwithin the first 12 hours. Up to 60% of patients reportdiarrhoea due to sympathetic blockade and unopposedparasympathetic efferent influence after coeliac plexusblock, which usually resolves within 48 hours [49]. Neuro-logic complications, including paraplegia, leg weakness,sensory deficits, and paresthesias, have been reportedafter coeliac plexus ablation and with a large study report-ing four cases of paraplegia after 2,730 coeliac plexusblocks [50]. Paraplegia was attributed to either direct injuryof the spinal cord during the procedure or spinal infarctionsecondary to spasm of the spinal artery.

Theoretically, radiofrequency splanchnic denervationshould avoid the risk of such paraplegia [51] but outcomeis less studied. It may be an option when relative risks arediscussed with the patient.

Superior Hypogastric Plexus Block

The superior hypogastric plexus carries afferent from thebladder, uterus, vagina, prostate, testes, urethra,descending colon and rectum. Superior hypogastric blockmay relieve pelvic pain and a block of these nerves hasbeen described to reduce pain associated with pelvicmalignancy [52]. Posterior approach is commonest but ananterior approach has been described [53].

Ganglion Impar Block

This is the most inferior sympathetic ganglion lying anteriorto the sacrococcygeal junction. It has been shown in caseseries to provide pain relief for patients with advancedcancers of the pelvis and perineum, after abdomino-perineal resection for rectal cancer [52] and followingradiation proctitis [54].

Neuraxial Blocks

Neuraxial blocks may be epidural (outside the theca ordura mater) or intrathecal (into the cerebrospinal fluid).

Epidural local anesthetic and steroid can provide tempo-rary pain relief where a vertebral metastasis is associatedwith nerve compression.

Care should be exercised if impending cord compressionor invasion of the epidural canal by tumor is suspectedand imaging may be advisable in such circumstances.

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Despite the lack of evidence to support these interven-tions, several experienced practitioners have and continueto use these techniques with reported benefit to patients.Epidurals with steroid and local anesthetic can providetemporary pain relief.

Intrathecal and Spinal Nerve Root Neurolysis

A saddle block with heavy intrathecal phenol can be usedfor perineal pain of somatic origin in advanced pelviccancers, especially where bladder and bowel function arealready compromised.

Chemical neurolysis of spinal nerve roots is used lessfrequently than in the past as safer interventions (e.g.,neuraxial infusions have been developed). While there arecase series describing effective relief of pain, the durationis limited and the incidence of neurological deficits is high[55].

Neuraxial Infusions

Some patients with advanced cancer may have pain thatcannot be controlled with systemic medications, or theuse of these medications may be limited by unacceptableside-effects at doses below those required to giveadequate relief. For these patients administration of drugsby the spinal route, either epidurally or intrathecally, maybe required and gives good control in the majority of cases[56].

There are different types of procedures ranging from per-cutaneous lines to fully implanted programmable pumps.The fully implanted systems carry less risk of infection andhave lower maintenance but the operation is more pro-longed [57]. Costs of the therapy currently suggestimplanted systems are more cost effective than the per-cutaneous after 3 months [58].

There is evidence from RCTs of improved pain relief andless drug related side-effects compared with medicaltherapy for fully implanted systems. The reversal ofdrowsiness associated with systemic opioids is of greatpractical significance [28,59,60].

These procedures carry a moderate level of minor adverseeffects and a low level of serious adverse effects [57]. Theyshould be reserved for those patients whose pain cannotbe controlled with systemic analgesia and undertaken incenters experienced with the technique and its aftercare[61].

The most effective drugs are opioids, commonly mor-phine, and generally patients who respond to spinal mor-phine are those who respond to systemic morphine butonly partially and/or are limited by dose related side-effects. Patients who are unresponsive to large doses ofsystemic opiods are unlikely to respond to spinal opioids.Other drugs that appear to be effective spinally includelocal anesthetics (typically bupivacaine) [62], alpha-2 ago-nists (clonidine) [63] and ziconotide [28]. In a randomized

placebo controlled study of Zicomotide in ill patients, 50%on active therapy vs 17% on placebo achieved >30% painrelief. However, 30% on ziconotide vs 10% on placeboexperienced “serious” side-effects, 38% of those onziconotide discontinued treatment, and follow-up gener-ally thought to be too short. Fuller details of the use ofintrathecal therapies is found elsewhere [61].

Intraventricular opioids can be administered via animplanted pump and catheter for pain in the head and face.Cerebrospinal fluid diversion via a shunt or third ventricu-lostomy may be appropriate for palliation in some cases ofobstructive hydrocephalus that are otherwise inoperable;craniotomy and subtotal removal of a malignant cerebraltumor is a routine neurosurgical palliative procedure.

Domiciliary Management of Spinal Catheters

Most patients want to die at home [64], and while the safemanagement of spinal drug infusions does present chal-lenges to this, these can be overcome to facilitate this aim[65]. In addition, with percutaneous drug delivery, intrath-ecal use allows lower dose and therefore longer intervalsbetween infusion refilling of ambulatory pumps, facilitatinghome care and reducing the risk of infection. Intrathecalcatheters may be less prone to dislodgement, and block-age due to fibrosis [66], and have been shown to be saferin the domiciliary setting [67].

Preparation

Full involvement of the primary care team in the manage-ment of pain is vital. If, when considering the use of spinaldrug delivery, management at home is identified as apriority it is essential to establish that the patient and familyare suitable and have appropriate goals and expectations.The community nursing and primary care teams should behappy to cooperate and be involved.

Psychological assessment should be considered oncepain has been relieved, and sedation due to analgesicsminimized, some patients may be less distracted from theother psychological aspects of their illness. This can leadto difficulties with good symptom control. Full discussionand consent from the patient and family, taking factorssuch as these into consideration, is essential.

Procedure

Percutaneous catheters, injection portals or fully implantedsystems may be used, but a factor in patient selection is theshorter expectation of survival in this group compared withpatients with nonmalignant pain. Percutaneous cathetersmay be tunnelled or nontunnelled: tunnelled catheters areless prone to displacement and infection [56].

Implantation and other procedures are ideally done in asterile facility with resuscitation facilities in a hospital orhospice. Insertion as a domiciliary procedure has beenreported [68], but this does raise issues with sterility andthe ability to resuscitate in the event of side-effects.

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Very compact and reliable battery-powered infusionpumps are available that allow both continuous andpatient-controlled bolus drug administration.

Aftercare

It is imperative that those who will be involved in thepatient’s management at home are fully trained and con-fident in the necessary techniques and knowledge beforedischarge. The patient’s management should also be sta-bilized as an inpatient or in hospice prior to dischargehome, with titration down of systemic analgesics, in par-ticular to avoid opioid overdosage [69]. The cooperation ofthe patient’s general practitioner and out of hours serviceis important, and this is supported by the availability ofdetailed guidelines or protocols, and back-up frommembers of the specialist pain or palliative care team isessential [61]. This should be recognized in job plans.

With appropriate training and compliance with competen-cies, refilling of infusion reservoirs can be performed bycommunity nursing staff, as well as monitoring of thepatient’s condition: particularly pain relief, temperatureand the state of implantation sites. Again, guidelines orprotocols should support this.

Anterolateral Cordotomy

This can be undertaken as a percutaneous or open pro-cedure involving intervention on the side of the spinal cordopposite to that of the pain to ablate the spinothalamictract fibers. Consequently, it reduces the sensation oftouch and temperature in addition to pain.

The awake percutaneous procedure ablates the spinotha-lamic tract using radiofrequency lesioning through a needleinserted between the first and second cervical vertebrae.Its value in mesothelioma is well documented [70] and itsuse in other lateralized pains is recognized [71].

Immediate pain relief is achieved in the majority with 80%either stopping or reducing opioids but pain recurs in a thirdof these by 6–12 months [70]. The main risk is of weaknessof the leg contralateral to the side of the pain throughdamage to the corticospinal tract, mild effects are seen inup to 8–10% in the first few days, but prolonged effects arereported in 1–2% [71]. This risk increases, for topographi-cal reasons, when the lower sacral dermatomes are tar-geted. Painful dysethesias occur in about 5% [70].

Whereas percutaneous cordotomy can only be performedin the cervical area, the spinothalamic fibers can bedivided by open operation in the thoracic cord. This avoidsthe risk to respiration and to the upper limb when the painis below the waist (e.g., secondary to invasion of thelumbosacral plexus and is recommended for bilateral pro-cedures to avoid fatal sleep apnoea). In a small series [72],none of the patients experienced motor weakness and allhad complete or nearly complete and sustained relief ofthe target pain, allowing a substantial reduction in medi-cation for all but one. This released them from being

closely tied to the hospital/hospice allowing greaterfreedom and independence that was dramatic in somecases (e.g., holidays abroad). There were no new sphinc-ter disturbances reported.

Midline Myelotomy

Splitting the spinal cord in the midline posteriorly wasintended to divide the spinothalamic fibers as theycrossed, thereby controlling bilateral pain while avoidingthe risks of bilateral cordotomy. Introduced in 1926, it wasnot particularly successful until the serendipitous observa-tion in 1970 that a single level myelotomy at C1 producedanalgesia over a wide body area. It was subsequentlyfound that a limited midline myelotomy at T10 was effec-tive against pelvic visceral cancer pain [73]. The recentdiscovery of a specific pathway in the medial dorsalcolumns which conducts visceral pain [74] provides apossible substrate for this operation that appears to bevery effective and safe [75] but is rarely used.

Other Neurosurgical Procedures

In the past, many surgical targets in the brain have beentried with varying degrees of success and morbidity, butnone is now used more than sporadically. This includessites in the medulla, pons, midbrain, thalamus and hypo-thalamus, and the somatosensory and cingulate cortices.The pituitary gland provided one of the most useful targets;transnasal alcohol-induced hypophysectomy was veryeffective against hormone-dependant and diffuse cancerpain particularly when due to bone metastases from breastand prostate. Diabetes insipidus occurred in half thepatients and visual disturbances were common; pharma-cological hormonal manipulation has made it redundant.Dorsal root entry zone lesions are rarely used for cancerpain; an extensive laminectomy is required, the morbidity isrelatively high, only paroxysmal pain responds well andcordotomy or rhizotomy are likely to be preferable.

Vertebroplasty

Painful pathological fractures of vertebra that do notrespond to the conservative therapies of medications,TENS, steroid epidurals can be considered for fixation bycemented vertebroplasty. Open studies in myeloma andmetaststic cancers report pain relief that is often completein around 80% of patients [76–78]. Cement leak is thecommonest risk at around 5%; however, complicationsfrom this are rare but are serious [79].

Complementary Therapies in Cancer Pain

Summary

There is a weak evidence base for the effectivenessof complementary therapies in terms of pain control, butthey may improve well being. Safety issues are also aconsideration.

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Introduction

Complementary and alternative medicine (CAM) refers toa diverse array of treatment modalities and diagnostictechniques. It has been defined as “diagnosis, treatmentand/or prevention which complements mainstream medi-cine by contributing to a common whole, satisfying ademand not met by orthodoxy, or diversifying the concep-tual framework of medicine” [80].

Large proportions of cancer pain patients are using CAM[81]. Reasons include dissatisfaction with conventionalmedicine, desperation, compatibility between the philoso-phy of CAM and patients’ own beliefs, and the wish formore control over one’s own health [82].

CAM therapies have the potential to increase well-beingand thus influence pain. They are often employed in addi-tion to conventional treatments in palliative and supportivecancer care.

Acupuncture

This is the insertion of needles into the skin and underlyingtissues for therapeutic or preventive purposes at specificsites, known as acupuncture points.

A systematic review identified two RCTs and found nocompelling evidence of acupuncture to control cancerpain [83] that was confirmed by other reviewers. Subse-quent RCTs did not produce convincing evidence of effec-tiveness. It is effective in alleviating chemotherapy-relatednausea and vomiting and may hence contribute to paincontrol [84].

Aromatherapy

Controlled use of plant essences, applied either to the skinthrough massage, added to baths or inhaled with steam-ing water.

A Cochrane systematic review concluded that aroma-therapy and/or massage has beneficial short-term effectson well-being in cancer patients [85]. It has, however, notbeen convincingly demonstrated whether it is associatedwith clinically relevant analgesic effects.

Herbal Medicine

Medical use of preparations, which contain exclusivelyplant material. There is no convincing evidence for anyherbal medicine to suggest effectiveness for treatingcancer pain [80].

Homeopathy

This is where diluted preparations of substances whoseeffects when administered to healthy subjects correspondto symptoms and clinical signs of the disorder in patients.

A systematic review of six RCTs found no convincingevidence that homeopathic remedies have analgesiceffects in cancer patients [86].

Hypnotherapy

This is the induction of a trance-like state to facilitaterelaxation and enhance suggestibility for treating condi-tions and introduce behavioral changes.

Studies have suggested the usefulness of hypnotherapy inpalliative cancer care. A systematic review found encour-aging evidence that hypnotherapy can alleviate cancerpain [87]. Due to the often poor methodology of theprimary data, this evidence was deemed inconclusive.Similar conclusions were reached in two systematicreviews for procedural pain in pediatric cancer patients[88,89].

Massage

This is the manipulation of the bodies soft tissue usingvarious manual techniques and applying pressure andtraction.

Massage seems to increase well-being through reductionof stress and anxiety levels and thus may contribute topain control. The evidence for analgesic effects in cancerpatients is encouraging but not convincing [90].

Music Therapy

The use of receptive (passive) and/or active music therapymost commonly based on psychoanalytical, humanistic,cognitive behavioral or developmental theory.

There is no convincing evidence from RCT data tosuggest effectiveness for pain control in cancer patients[80].

Reflexology

The use of manual pressure applied to specific areas, orzones, of the feet (and sometimes the hands or ears) thatare believed to correspond to other body areas or organs.

A few small RCTs generated no convincing evidence thatreflexology improves quality of life or pain of cancerpatients [91].

Relaxation

Techniques for eliciting the relaxation response of theautonomic nervous system resulting in the normalizing ofblood supply to the muscles, decrease in oxygen con-sumption, heart rate, respiration and skeletal muscle activ-ity. Most commonly progressive muscle relaxation is used.

Relaxation techniques have the potential to increase well-being and thus may contribute to controlling pain.

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Whether these techniques have direct analgesic effectsremains, however, unknown.

Supplements

Oral medical use of preparations of herbal or nonherbalorigin.

A systematic review of nine RCTs that tested cannabinoidsconcluded that they are not superior to codeine in con-trolling cancer pain. As cannabinoids cause centralnervous depression their introduction into routine carewas deemed undesirable [92].

Safety Issues

Complementary therapies are often used because theyare erroneously considered safe and harmless, which canbe dangerously misleading. Some treatments like home-opathy, massage, music therapy, reflexology and relax-ation are associated with only mild and rare direct risks ifadministered appropriately by a trained practitioner.Others have been associated with potentially serious risks:herbal medicines and supplements with herb-drug inter-actions, toxicity and contamination, acupuncture withpneumothorax, hypnosis with negative physiological andpsychological effects. General safety issues include mis-diagnosis, or delayed access to effective treatments. Self-medication is another problem due to the potentialinteractions with conventional cancer treatments. Also,patients often do not disclose their use of complementarymedicines to their health care provider who needs to seekthe relevant information.

Cancer Pain Management in the Community

Summary

Patients with cancer pain spend most of their time in thecommunity until the last month of life. Overall cancer painprevalence in the community in Europe is 72%. Olderpatients and those in care homes may particularly haveundertreated pain. Primary care teams supported by pal-liative care teams are best placed to initiate and managecancer pain therapy, but education of patients, carersand health care professionals is essential to improveoutcomes.

Introduction

Managing patients with cancer pain in secondary or ter-tiary care settings has several advantages compared withmanagement in community settings (defined as thepatient’s home, care-homes or hospices). These advan-tages include more comprehensive assessment andobservation, better access to investigations, and moredirect influence on prescribing and administration oftherapy.

Increasingly however, patient’s wishes and U.K. govern-ment policy advocates improved palliative care, and there-

fore cancer pain management, for patients in thecommunity. Hospice patients consistently rate pain man-agement as a top research priority within palliative careabove other symptoms and aspects of care [93]. Anunderstanding of cancer pain management in the com-munity is therefore important for planning services andinterventions.

Epidemiology of Cancer Pain in the Community

Prevalence

Systematic reviews [94,95] have demonstrated thatcancer pain is common and its prevalence is related to thestage of illness: 48% of patients with early disease; 59%undergoing cancer treatment; 64–74% with advanceddisease. These findings are in keeping with those in therecent European Pain in Cancer (EPIC) survey of 11 Euro-pean countries, which indicated an overall pain prevalenceof 72% of patients with cancer in the community. This wasslightly higher in the United Kingdom at 77% [96].

Pain Severity

Most research on cancer pain severity has been con-ducted in secondary care settings [97,98]. Using a 0–10numerical rating scale, hospitalized cancer patients typi-cally report mean scores for worst pain 4.8, mean scorefor average pain 3.7, worse pain intensity greater than 5 intwo thirds of patients.

There has been less research in community basedpatients with cancer pain. The EPIC survey invited patientswith cancer pain in the community to participate that werespecifically not recruited through palliative care or painservices [96]. For the 617 patients from the UK, the meanpain intensity was 6.4 (identical to the European average);over 90% rated their pain greater than 5 out of 10; aquarter were not receiving any analgesia.

This survey suggests that community based patients havegreater, not less, pain intensity than those in secondarycare and highlights the need for effective strategies inprimary care.

Effects of Age on Pain and Treatment

Concerns exist that older people with cancer experienceless effective pain management than younger people[99–101]. Recent research suggests that when olderpeople with cancer are compared with a younger groupthere is no significant difference in pain intensity [98,102–105]; older people with cognitive impairment reportgreater intensity of cancer pain than those without [106];older people are less likely to receive adequate analgesiathan younger people [107,108] but importantly, thesestudies only compared the category of the analgesic pre-scribed for a given pain intensity, and not on the basis ofwhether the analgesic therapy was effective in reducingpain.

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Further research into the differences in analgesic prescrib-ing between older and younger people has shown thatolder people generally require lower doses of analgesia,especially opioids, than younger people even when con-trolling for pain intensity [102–104,109]. This may be dueto a physiological phenomenon, for example, impairedanalgesic metabolism and excretion. Older people maysometimes need higher doses; 58 older people aged over75 years attending a German pain clinic received higherdoses of opioids than those aged under 65 years [110].Older people do not experience more adverse effects,dose escalation or the need for opioid switching, thanyounger people [103,110]. Older people may have poorerattitudes and knowledge about pain and analgesia thanyounger people and therefore, are reluctant to have stron-ger analgesia [111,112].

In summary, age does not appear to impact upon painintensity, but older age does appear to be associated withlower doses or potency of analgesic therapy in secondarycare settings. These settings include hospital or hospiceinpatient units and out-patient clinics. There is a paucity ofresearch on community based patients with cancer pain.

Time Spent by Patients in the Community

Patients with cancer pain spend most of their time in thecommunity. RCTs from Italy and Norway that have exam-ined the impact of home-based palliative care teams haveshown that in the last 6 months of life patients referred tosuch teams spend between 65 and 81% of time at homecompared with 65–70% of time in a control group; lesstime was spent at home and more time in hospital in thelast month of life [113,114].

Primary care teams supported by home-based palliativecare teams are therefore usually best placed to initiate andmanage cancer pain therapy for the majority of patients.

Barriers to Pain Management

Patient Based Barriers

Attitudes or behaviors that prevent successful pain man-agement are referred to as barriers and can be assessedusing the Barriers Questionnaire (BQ) [115,116]. Researchsuggests that the most important of these barriers are fearof consequences of analgesic use (addiction and toler-ance), fatalism about pain, inadequate communicationwith health care professionals, some religious and culturalbeliefs may also impede effective pain control [117,118].

However, a U.K. study [112] which interviewed older andyounger patients with cancer pain at home highlightedthat knowing when to take and titrate analgesia was themost important barrier for all ages; older people foundtaking and titrating analgesia significantly more of a barrierthan younger people; fear of adverse effects was animportant barrier for both groups; fatalism and communi-cation issues where of less importance.

Role of Carers

Carers and family members are important sources ofsupport for patients with cancer pain. However, carers canhave a powerful influence on the management of pain inan individual patient. Carers’ barriers are often similar innature to patient barriers but also include hesitancy toadminister analgesia. Ethnicity of carers may also influ-ence BQ scores.

High scores by carers on the Barriers Questionnaire havebeen shown to more strongly predict inadequate cancerpain management than patient scores (based on patientpain scores and level of analgesia); be associated withreports from carers that a patient’s pain is uncontrolled[119,120].

Health Care Professionals

Knowledge and attitudes of health care professionalstoward cancer pain management vary. When these havebeen compared directly [121,122] nurses have beenshown to have better pain assessment skills than doctorsor pharmacists; doctors had better knowledge about clini-cal therapy; pharmacists had most knowledge aboutopioid pharmacology; all three professional groups scoredpoorly in some area.

These comparisons demonstrate the need for clinicalteams rather than individuals to be involved in managingcancer pain.

Place of Care

Primary care or community settings include care homes(nursing or residential) and patients with cancer pain in thiscontext can sometimes be at a disadvantage. There is ahigh prevalence of daily pain in nursing home residentswith cancer and this is often untreated, particularly in olderpatients [108]. Nursing homes can vary in their level ofstaffing and equipment (e.g., syringe drivers) necessary foreffective cancer pain management particularly at the veryend of life.

Access to Opioids

Opioids are central to effective cancer pain managementbut access to opioids in the community may be an addi-tional barrier faced by patients. In the United States, phar-macies in predominantly ethnic minority areas aresignificantly less likely to carry sufficient opioids than inother areas [123,124]. There is no comparative data spe-cific to the UK.

Patient-Based Educational Interventions

Types of Interventions

Interventions designed to improve knowledge and atti-tudes toward cancer pain and analgesia have beenstudied extensively. These have been a combination of a

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brief coaching session (20–40 minutes) in which patient orcarer barriers are indentified and addressed, with adviceon using analgesia; supported by written material andoccasionally audiovisual material that patients and carerscan review at home. Some studies have examined moreintensive interventions that consist of repeated coachingand support by a nurse or researcher. Comparators inthese randomized trials have included either usual care ora placebo such as a booklet on nutrition.

Evidence of Effectiveness

A recent meta-analysis of 21 clinical trials [125] has shownthat educational interventions for community patients withcancer pain significantly improve knowledge and attitudestoward pain and analgesia, and reduce pain intensity.Compared with control, educational interventions resultedin a mean reduction of around 1 point on a 0–10 numericalrating scale for both worst and average pain intensity;produced a similar effect to that seen when adding parac-etamol or gabapentin to patients already treated withopioids [126,127].

Patient and carer education is therefore an important,though probably under-used, component of successfulcancer pain management.

Pain Related to Cancer Treatments

Summary

Chemotherapy, surgery and radiotherapy are cancer treat-ments that can cause persistent pain in cancer survivors,up to 50% of whom may experience persistent pain thatadversely affects quality of life. Awareness of this problemmay lead to preventative strategies, but at the moment,treatment is symptom based and often inadequate.

Introduction

Chemotherapy, surgery and radiotherapy are cancer treat-ments that can cause persistent pain in cancer survivorpatients and adversely affect quality of life and function.

Up to 50% of cancer survivors may experience chronicpain secondary to treatment yet this is under recognizedand under reported [128]. Pain in cancer survivors has anadditional burden in that it is often perceived to be indica-tive of disease recurrence.

Painful Chemotherapy-Induced PeripheralNeuropathy (CIPN)

Neurotoxicity is a dose limiting side-effect of many che-motherapies and biological therapies (also known as bio-logical response modifiers that modulate the naturalresponse to tumor cells) used in the treatment of cancer.Peripheral neuropathy is the most prevalent form ofneurotoxicity.

Risk Factors for Development of CIPN

Longer duration of therapy; high cumulative dose; type ofchemotherapeutic agent (e.g., vincristine, cisplatin, pacli-taxel); pre-existing neuropathy (including CIPN).

Common Features of CIPN

Symmetrical symptoms; length dependency: “stocking-glove” distribution, distal limb long nerves affected; signsand symptoms of neurosensory dysfunction; onset relatedto administration of neurotoxic therapy: rapid, or delayedor even after therapy has finished; relative sparing of motorfunction [129].

In addition to interference with microtubular mediatedaxonal transport and anatomical damage, alterations innerve function mediated by pro-inflammatory cytokines,immune cells and mitochondria have been postulated asimportant in CIPN [130,131]. Pain is not synonymous withneuropathy but is associated with higher grades of periph-eral neuropathy.

Assessment

Several assessment tools have been used and validated[132]. Many are clinician rather than patient based and donot all include assessment of pain, function and quality oflife. A specific CIPN pain scale could reduce under-reporting and therefore undertreating of CIPN pain.

Quantitative sensory testing (QST) does not always reflectsymptoms or correlate with chemotherapy dose nor doesit identify neuropathy earlier than clinical history andexamination [129]. However, QST is an objective assess-ment that is useful for surveillance of recovery (Table 1).

Prevention and Treatment

Modification and refinement of chemotherapy dosageschedules (especially in palliative setting) can reduceCIPN. Specific preventative treatments such as amifos-tine, glutathione, N acetyl carnitine, N acetyl cysteine,glutamine/glutamate have been studied in humans andanimal models with variable success. Vitamin E canreduce cisplatin and paclitaxel induced neuropathy[136,137]. More research is needed to ascertain effectiveagents without appreciable side-effects or affecting anti-cancer efficacy.

Supportive education and nonpharmacological treat-ments are important. Simple strategies to reduce theimpact of numb and painful hands and feet, such asreducing water temperature, using aids to help holdingcups and utensils, are important. Psychological support,physiotherapy and occupational therapies are part of amultidisciplinary approach.

There is few data on effective pharmacological treat-ments of CIPN. Current management is predominantlybased on evidence from other neuropathic pain. Although

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gabapentin was effective in an animal model of CIPN[138], it had no effect in humans in a controlled, random-ized crossover trial [139]. Until there is more data, currentneuropathic pain treatment guidelines may be used [140–142]. However, mechanisms of CIPN may be different toother neuropathic pain and more research is needed.

Post Cancer Surgical Pain

Pain syndromes after cancer surgery are found followingbreast, thoracic, head and neck surgery.

Post Breast Cancer Surgery Pain (PBCSP)

Chronic pain following surgery for breast cancer has beenreported with an incidence of over 50%. Similar to otherpain in cancer survivors, it is under reported, under rec-ognized and undertreated. Classification is varied andpotentially confusing, yet PBCSP is likely to be predomi-nantly neuropathic in origin, secondary to surgicaldamage. Pain can occur in the scar, arm, chest wall or thebreast and is commonly associated with sensory distur-bance. Pain often interferes with function and quality oflife.

Risk Factors. Various risk factors predicting the develop-ment of PBCSP have been suggested, although data areconflicting: young age (although may be linked with moreaggressive disease and treatment), previous chemo-therapy and radiotherapy, poorly controlled post operativepain, pre-existing anxiety and depression and surgicalfactors.

Surgical Factors. Damage and dysfunction of the intercos-tobrachial nerve has been proposed as the main mecha-nism for PBSCP. Some studies showed lower incidence ofpain after preservation of the nerve. Thirty per cent stilldevelop pain after preservation, and 30% do not developPBCSP after the nerve is cut. Pain is less common aftersentinel node biopsy compared with axillary dissection[143].

Surgical factors are influenced by their impact on postoperative pain. Certain studies found that breast conserv-ing surgery led to less chronic pain than more radicalsurgery, but others have suggested the opposite[144,145].

Reconstructive surgery may be an additional risk factor;however, few studies have examined the more contem-poraneous free flap techniques such as the deep inferiorepigastric perforator flaps. Postoperative pain followingDIEP flap is less than after latissimus dorsi flap and there-fore putatively associated with less chronic pain.

Treatment and Prevention. Reduction of risk factors for thedevelopment of PBSCP such as attention to good postoperative pain control, careful choice of surgical proce-dure and meticulous technique could reduce PBSCP.Ta

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A few small trials of treatments for PBSCP have demon-strated modest and variable benefits from capsaicin andEMLA cream, gabapentin, amitriptyline and venlafaxine.Nevertheless, treatment includes best practice for generalneuropathic pain management in a multidisciplinaryapproach.

Post Thoracotomy Pain

Persistent pain following thoracotomy for malignant andnonmalignant indication may occur in more than 50% ofpatients [146] and as for other types of chronic postop-erative pain may be related to perioperative nerve damage[147]. Similarly, postoperative pain is a risk factor forchronic pain. Video-assisted thoracoscopic lung surgery(VATS) is associated with a lower incidence of persistentpain.

Post Head and Neck Surgery Pain

Surgery, in addition to chemotherapy and radiotherapy, isassociated with chronic long-term pain for patients withhead and neck cancer. Pain can occur in the oral cavity,face neck or shoulder. The incidence of chronic pain aftersurgery is similar to other post cancer surgery pain, about40% at 1 year and 15% at 5 years [128]. Of the 33% ofpatients who had pain 1 year after neck dissection, mosthad features of neuropathic pain [148]. Treatmentdepends on careful assessment, providing information topatients and a combination of physical and pharmacologi-cal approaches.

Radiotherapy Induced Pain

Radiotherapy is used as a primary adjunctive treatment formany types of cancer. Certain tissue such as skin,mucous membranes and nerves, are more susceptible todamage.

Radiation-Induced Brachial Plexus Neuropathy (BPN)

Radiation-induced BPN was associated with breast con-servation strategies and deep delivery of radiotherapy inthe 1960s and 1970s. Modification of radiotherapy treat-ments have reduced the incidence of BPN [149,150]. BPNusually occurs at least 6 months after therapy, althoughhigher doses may have a reduced latency. The majordifferential diagnosis is tumor related plexopathy. In addi-tion to clinical factors, MRI may aid diagnosis.

Features Suggestive of Radiation-Induced Neuropathy.Progressive forelimb weakness (upper or lower armdepending on which roots are involved), pain lesscommon, initial involvement of upper plexus divisions,slow progression and long duration, and incidenceincreases with time.

Treatment. There are no standard treatments for radiation-induced BPN but opioids may be beneficial [151]. Othernonpharmacological treatments such as chemical sympa-

thectomy have been used, but evidence is limited. Currenttherapies are also based upon existing treatments forother neuropathic pain.

Pelvic Pain after Radiotherapy

Radiotherapy for pelvis malignancy can also lead toradiation-induced chronic pain syndromes. Pain resultsfrom multiple mechanisms, including effects on gut,nerves and pelvic and hip fractures. Dysuria may occur in20% of patients 1 year after pelvic radiation [128]. In onestudy, nearly 50% of patients reported pain in back andlower extremities which was poorly controlled with anal-gesics and had a negative influence on quality of life [152].Treatment is symptom-based although, as for BPN, pre-ventative strategies are being explored.

Management of Acute Pain in Cancer Patients

Summary

Management of acute pain, especially postoperative pain,in patients on high dose opioids is a challenge thatrequires in depth knowledge of pharmacokinetics andformulation of a careful management plan to avoid with-drawal symptoms and inadequate pain management.

Introduction

Patients with cancer who present for surgery on high doseopioids are a heterogeneous group with a number ofcomplex perioperative analgesic management problems.The main issues include: physical dependence and theprecipitation of withdrawal symptoms if insufficient post-operative opioid is prescribed, and tolerance to the effectof postoperative opioids. Additionally there may be diffi-culties in calculating dosage conversions between differ-ent types of opioid and different routes of administration.

Tolerance

Tolerance is a phenomenon in which exposure to a drugresults in the diminution of an effect or the need for ahigher dose to maintain an effect. It may develop 1–2weeks or more after initiation of opioid therapy. A largerdosage of opioid will be required to achieve the desiredeffect. Short-acting opioids should be titrated to effect in acontrolled, monitored environment.

Tolerance also develops to some of the side-effects ofopioids making patients less likely to suffer from respira-tory depression, itching and nausea than opioid naïvepatients.

Acute Pain Management

Management of pain in this population of patients is ofincreasing importance as the cancer survivor populationgrows and as greater numbers of patients are using con-venient sustained release opioid preparations and trans-dermal delivery systems.

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In general the issues of physical dependence, withdrawaland tolerance, only relate to patients who have been onWHO Step 3 strong opioids such as morphine or oxyc-odone for more than 1–2 weeks preoperatively. Theseissues are not likely to be a problem in patients takingWHO Step 2 analgesics such as codeine or tramadolunless the patient is taking larger than normal doses.

It is common to underestimate and undertreat pain inopioid dependent patients, because most postoperativeanalgesic regimes are based on the opioid naïve patient.Opioid dependent patients should be identified preopera-tively and a perioperative analgesic plan should bedevised after discussions with the patients’ opioid pre-scriber and with the pain team. The aim is to achieveeffective analgesia without precipitation of withdrawalphenomena.

Opioid Management

Management involves the regular provision of the pre-existing opioid supplemented with additional short-actingopioid, local anesthetic, nonsteroidal anti-inflammatorydrug and paracetamol. Patient-controlled analgesia with ashort lock-out and higher bolus dose may be useful.Neuraxial and regional analgesia is recommended whereappropriate.

Patients will present for surgery having been on manydifferent types of opioid for varying periods of time (e.g.,morphine, oxycodone, methadone, hydromorphone,pethidine, etc.) which may be modified release (e.g., MST,fentanyl patch) or immediate release preparations (e.g.,immediate release morphine). The route of delivery may beoral, subcutaneous via a syringe pump or transdermal.Dosages range from MST 10 mg twice a day to very largedoses such as MST 1 g per day or more.

Standard postoperative opioid regimes are generallydeveloped for the opioid naïve patient. Patients on highdose opioids may have developed a physiological depen-dence and if managed using standard postoperative anal-gesia regimes may not receive adequate analgesia anddevelop a “withdrawal syndrome.” This results in adrener-gic hyperactivity and common symptoms such as fatigue,generalized malaise, abdominal cramps, perspiration,fever, piloerection, dehydration and restless sleep.

Patients will require a baseline opioid dosagepostoperatively—referred to as the baseline opioidrequirement—calculated using their preoperative opioiddosage. This can either be given using the same opioid orusing an alternative opioid in an equi-analgesic dosage. Acontinuous parenteral infusion may be needed if thepatient is unable to take oral drugs. Provision will need tobe made for “as required” dosing for breakthrough pain.Patient controlled analgesia machines have been suc-cessfully used in opioid dependent patients, their advan-tage is that dosages and lock-out intervals can beadjusted according to need.

In the preoperative and perioperative period regularopioids (usually oral) may be discontinued for severalhours which amounts to the opioid “debt.” This should bereplaced with systemic opioids during the operation.

Parenteral Opioid Delivery. Transdermal drug deliverysystems have the disadvantage of being relatively inflex-ible in their dosage delivery, with clinically relevantdosages still being absorbed for up to 12 hours. Onestrategy is to leave the patch in place and to titrate toanalgesic effect using immediate release opioids. Similarly,it may be appropriate to leave implanted analgesic pumpsthroughout the perioperative period and use additionalshort acting opioid and nonopioids used to control break-through pain.

Nonopioid Analgesia

Nonopioid analgesic drugs and local anesthetic proce-dures will have the effect of reducing opioidrequirements—“opioid sparing effect” (e.g., nonsteroidalanti-inflammatory drugs [NSAIDs], paracetamol and cloni-dine). Local anesthetic blocks such as epidurals, brachialplexus block, paravertebral or ilioinguinal blocks will alsohave an “opioid sparing” effect.

Effects of Surgery

Surgery itself will have a variable effect on opioid require-ments and parenteral routes will have to be considered ifthe oral route is not available. It is difficult to predict theprecise postoperative analgesic requirements as the effectof surgery may be to increase (if the surgery results in paindue to local tissue trauma) or decrease opioid require-ments. Increases of 20% or more above the baselineopioid requirement have been reported, depending on thesurgical procedure. However, surgery may alleviate paindue to removal of direct tumor pressure effects on localstructures (e.g., removal of a retroperitoneal sarcomatumor pressing on the lumbosacral plexus). In this groupof patients opioid requirements may reduce but they willstill need baseline opioid administration.

Complex Problems in Cancer Pain

Summary

Cancer pain is often very complex but the most intractablepain is often neuropathic in origin, arising from tumorinvasion of the meninges, spinal cord and dura, nerveroots, plexuses and peripheral nerves. Accurate diagnosisof the causes of pain is necessary with the use of multi-modal therapies. Case studies illustrating some of thesepoints are found in the British Pain Society document(http://www.britishpainsociety.org).

Introduction

Cancer pain can be complex and difficult to treat. Up to50% of patients may have pain at diagnosis and greaterthan 75% may experience pain with advanced cancer.

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Pain may occur in more than one site in over half of casesand may have different etiologies. Such complexity can bechallenging and require a truly multidisciplinary approach.As for nonmalignant pain, management of cancer paincan be challenging for the very young or old, for patientswith medical problems such as heart disease, respiratorydisease, renal or liver compromise and those with mentalhealth issues. Often these factors may present in combi-nation and generate demanding clinical problems.

Certain pain problems related to the nature of the pain orpatient factors, may make the conventional WHO ladderapproach to pharmacological therapy difficult to utilize andin some cases this approach may not be totally effective.Other pharmacological or more invasive treatments maybe required.

To exemplify such complex issues we will discuss casestudies concerning problems of breakthrough pain;cancer pain control in patients addicted to opioids; treat-ment of pain of mucositis; cancer pain in patients withdementia; alternatives to the conventional WHO ladderapproach; interventional procedures; ketamine.

Breakthrough Pain

Breakthrough pain has been referred to as a brief exacer-bation of pain on a well controlled baseline. The terminol-ogy of “breakthrough pain” in undergoing subtle revisionsbut is made up of many different types of pain. Break-through pain can be of any etiology. Certain authors feelthat “breakthrough pain” does not include exacerbationsof pain in the titration phase, nor should end of doseexacerbation of pain be called “breakthrough” [153].

Breakthrough pain can be divided into spontaneous: noobvious cause; incident pain: clear cause evident; nonvo-litional: pain caused by involuntary act; volitional: paincaused by voluntary act; procedural: pain caused bytherapeutic procedure.

As for any cancer pain, treatment relies on detailedassessment and formulation of a multidisciplinary therapyplan. Rapid acting opioids have been successfully used totreat breakthrough pain, but it remains a difficult therapeu-tic problem. Newer preparations of rapid release opioidsare being developed.

Pain in Opioid Addiction and Substance Misuse

In the United Kingdom, the prevalence of drug misuse isaround 9 per 1,000 of the population aged 15–64 years,and around 3 per 1,000 inject drugs, in most casesopioids. Opioid abuse and dependence are associatedwith a wide range of problems, including overdose, HIVinfection, hepatitis B or C, thrombosis, anemia, poor nutri-tion, dental disease, infections and abscesses, criminalbehavior, relationship breakdown, unemployment, impris-onment, social exclusion and prostitution.

Pain from Cancer in People Who are Addictedto Opioids may be Undertreated for theFollowing Reasons

Lack of understanding of opioid addiction and methadonemaintenance; lack of training on prescribing analgesia inthis group of patients; attitude of health care professionalsabout illicit drug users (fear of diversion); failure to recog-nize the potential for tolerance to other opioids inMethadone-maintained patients; acute pain may beundertreated leading to misunderstandings, patientanxiety, depression, dissatisfaction and complaints.

Principles of Giving Analgesia inOpioid-Addicted Patients

Prevent withdrawal symptoms/complications; assessopioid load (in an intravenous [i.v.] drug user this is difficult;withdrawal symptoms can be prevented with low doses ofopioids).

Diagnose the cause of the pain; nociceptive, inflammatory,neuropathic, visceral, mixed. Use balanced analgesiawherever possible (NSAIDs, paracetamol, local anesthet-ics, tricyclic antidepressants, anticonvulsants). Use oral/transdermal/subcutaneous routes, not i.v. (considerepidural or intrathecal drug delivery systems, remember-ing infection risk).

Use long acting opioids and minimize analgesia for break-through, as this may be rapidly escalated. Set a limit andreview frequently. Use tablets (sevredol, oxynorm) forbreakthrough pain, not oramorph.

Make a “contract” with the patient before starting therapy,explaining the limitations, and setting a clearly definedupper limit of opioids before next review. Write clearinstructions for the whole team.

Use a sole prescriber (usually GP). Prescriptions may haveto be issued daily, every 2–3 days, or weekly.

Use psychological therapies and treat anxiety anddepression.

Maintenance Therapy

Methadone substitution is the primary maintenance treat-ment in the UK, usually 60–120 mg daily. There may betolerance to other opioids, and rapid escalation of dosescan be dangerous, especially when combined withalcohol or other sedative drugs.

Naltrexone (opioid antagonist) is used in detoxificationprogrammes to help maintain abstinence. It is long acting(>48 hours) and will lead to opioid resistance and thenopioid sensitivity when it has been eliminated systemically.

Buprenorphine (partial agonist) is also used to preventwithdrawal symptoms in opioid dependent patients. Itsaction on the m receptors reduces the effects of any

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additional opioids. Average maintenance doses rangebetween 12 and 24 mg daily. Patients with severe cancerpain may have to be changed from buprenorphine tomethadone.

Mucositis

Mucositis is the painful inflammation and ulceration of themucous membranes usually in the mouth but can affectother areas of the mucosa in the gastrointestinal tract[154,155]. It can be caused by radiation therapy or che-motherapy and very common after radiotherapy forcancer of the head and neck and after certain types ofchemotherapy such as 5-fluorouracil. High dose chemo-therapy and hematopoietic stem cell transplantation haveespecially high incidence of oral mucositis [155,156].

Nonpharmacological treatment strategies include meticu-lous oral hygiene, gel-based barrier protection, reductionof known painful precipitants (e.g., alcohol), local anes-thetic mouth washes and other oral lubricants. Opioidsprovide the mainstay of pharmacological treatment butnewer anti-inflammatory therapies are being developed.However, severe oral mucositis often causes difficulties inswallowing precluding the use oral medication.

Pain in Dementia Sufferers

Adults with dementia will probably express their pain inways that are quite different from their cognitively intactcounterparts that can result in inadequate pain assess-ment and consequently poor pain management.

The processing of sensory-discriminative aspects of painin the brain are thought to occur in the lateral pain system,whereas motivational-affective aspects are processed bythe medial system. The recognition of these two systemsis important with patients with dementia. Pain thresholds(that are the sensory-discriminative aspects) do not differbetween patients with Alzheimer’s disease and thoseolder adults without dementia, although pain tolerance(motivational-affective aspect) does. Older adults withAlzheimer’s disease perceive the presence of pain, but theintensity and affective aspects are different to that expe-rienced by their cognitively intact counterparts. This mightexplain the atypical behavioral responses observed in thisgroup.

Observation of behavior for pain assessment in patientswho do not have the ability to communicate their pain canbe helpful but typical pain behaviors may be absent ordifficult to interpret. Involvement of health care profession-als, informal care providers and the family in the identifi-cation of pain is essential.

The American Geriatric Society [157] list six categories ofpain behaviors and indicators for older people withdementia: facial expressions; verbalizations and vocaliza-tions; body movements; changes in interpersonal interac-tions; changes in activity patterns or routines; mentalstatus changes.

A number of behavioral pain assessment tools for detect-ing the presence of pain in patients with dementia exist.Care providers are advised to select a tool that is appro-priate to the patient that can be used for initial andongoing assessments. However, the assessment ofbehavioral pain indicators should consider only one strat-egy to identify pain in patients with dementia and shouldbe used in conjunction with other pain assessment strat-egies and the evaluation of pain relieving interventions.

Atypical Pharmacological Treatments: Ketamine

The N-methyl-D-aspartate (NMDA) receptor has beenimplicated in mechanisms of neuropathic and inflamma-tory chronic pain. It is one of the key components ofcentral sensitization that contributes to increased pain andabnormal pain perception. It is also thought to be involvedin many cancer pains. When the conventional WHO ladderapproach fails, NMDA receptor antagonists could providea novel and powerful site of analgesia.

There is evidence for the efficacy of NMDA receptorantagonists in many chronic pains (including cancer pain),yet the situation is not so clear clinically. There are fewNMDA receptor antagonists available. Dextromethorphanhas been used for acute pain. Methadone also has someNMDA antagonist activity and may help in some cases ofopioid refractory pain. However, ketamine is the mostused NMDA receptor antagonist for cancer pain.

Ketamine is an anesthetic, but in smaller doses appears tohave analgesic properties. There are many case reportsand case series demonstrating significant efficacy inrefractory cancer pain either alone or concomitantly withopioids. However, there is little higher quality evidence(such as RCTs) at present. The lack of data is reflected inthe variability of suggested protocols in both dose androute of administration. Side effects are potentially prob-lematic including tachycardia and cognitive disturbancessuch as hallucinations. Nevertheless, ketamine mayprovide some empirical benefit in refractory cancer pain.

Pain in Children and Adolescents with Cancer

Pain in children and adolescents with cancer is a signifi-cant, debilitating, acute and chronic symptom, during orafter treatment that affects the quality of life of youngpatients and their families. In recent years, advances inpain management have been made, however, still pain isoften undertreated and there is a need for improvement.

The principles of pain management and palliative care inadult practice are relevant to pediatrics, nevertheless, theadult model cannot be applied directly to children for thefollowing reasons [158]: 1) the types of malignancy anddisease trajectory in children are different from those inadults; 2) special considerations are required when select-ing analgesics, doses and modalities during childhood.Factors that influence prescribing are quite distinctive fromadults and include metabolism, renal clearance, changingsize and surface area, and the ability to manage medica-

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tion, among others; 3) a child’s family and social context isdifferent to that of an adult: relationships with parents andsiblings, school and friends, extended family network areof paramount importance when treating young patients; 4)children’s developmental stage and continuous psycho-logical, spiritual and cognitive development need to betaken into account when treating their pain (e.g., a child’sconceptualization of what causes and eases pain, under-standing of time, ability to implement behavioral and cog-nitive strategies for coping with pain) and 5) the legal andmoral positions regarding the decision-making ability ofboth those with parental responsibility and the child/young person themselves is very different to that of anadult.

Effective pain management in children and young peoplewith cancer requires that pediatric health care providerstake into account the multitude of physiological and psy-chological changes that occur from infancy through ado-lescence, including changes in relationships with parents[159]. The multidisciplinary approach to providing painmanagement for children and adolescents includes inte-grating pharmacological and psychosocial care in thecontext of each patient’s physical, cognitive, emotionaland spiritual level of development [160].

Every child/young person with pain management and pal-liative care needs should have access to universal pedi-atric services, core palliative care services (hospice,community palliative care nurses) and specialist palliativecare support when required [161].

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