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

Cancer Pain: Part 2: Physical, Interventional and Complimentary Therapies; Management in the Community; Acute, Treatment-Related and Complex Cancer Pain: A Perspective from the British Pain Society Endorsed by the UK Association of Palliative Medicine and the Royal College of General Practitioners

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Jon Raphael, MB, ChB, MSc, FRCA, MD, FFPMRCA,* ‡‡Palliative Medicine, University of Sheffield, Sheffield, † Joan Hester, MB, BS, FRCA, MSc, FFPMRCA, UK; Sam Ahmedzai, BSc, MB, ChB, FRCP,‡‡ Janette Barrie, RN, MSc,§§ Paul Farqhuar-Smith, MB, BChir, FRCA, PhD, FFPMRCA,‡ John Williams, §§Long Term Conditions, Lanarkshire Health, MB, BS, FRCA, FFPMRCA,‡ Catherine Urch, BM, Scotland; MRCP, PhD,§ Michael I. Bennett, MB, ChB, MD, ¶¶ ¶ FRCP, FFPMRCA, Karen Robb, BSc, PhD, MCSP, ¶¶ Brian Simpson, MA, MB, BChir, MD, FRCS,*** End of Life Observatory, Lancaster University, Max Pittler, MD, PhD,†††† Barbara Wider, MA,††† Lancaster, UK; Charlie Ewer-Smith, DipCOT, CMS,‡‡‡ James DeCourcy, MBBS, FRCA,**** ***Neurosurgery, University Hospital Wales, Cardiff; Ann Young, MB ChB,**** Christina Liossi, BA, MSc, MPhil, DPsych,§§§ Renee McCullough, BM, BS, MRCP, DIP, PAL, MED,** Dilini Rajapakse, MBBS, †††Complimentary Therapy, Peninsula Medical School, MSc, MRCPCH,** Martin Johnson, MB, ChB, Exeter, UK; MRCGP,†† Rui Duarte, BSc,* and Elizabeth Sparkes, BSc¶¶¶ ‡‡‡Occupational Therapy, University Bristol Hospital, Bristol, UK; *Faculty of Health, Birmingham City University, Birmingham, UK; §§§Psychology, Southampton University, Southampton, UK; †Pain Management, Kings College Hospital, London, UK; ¶¶¶Psychology, Coventry University, Coventry, UK;

‡Anaesthetics, Royal Marsden Hospital, London, UK; ****Pain Management, Gloucestershire Hospital, Gloucester, UK; §Palliative Medicine, St. Marys Hospital, London, UK; ††††Science, German Institute for Quality and ¶Physiotherapy, St. Bartholemews Hospital, London, Efficiency in Health Care, Cologne, Germany UK; Reprint requests to: Jon Raphael, MSc, MD, **Paediatric Palliative Medicine, Great Ormand Street Birmingham City University, Faculty of Health, Hospital, London, UK; Graduate School, Ravensbury House, Westbourne Road, Westbourne Campus, Edgbaston, Birmingham ††General Practice, Royal College of General B15 3TN, UK. Tel: +44(0)1384 244809; Fax: Practitioners, London, UK; +44(0)1384 244025; E-mail: [email protected].

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Abstract This document is accompanied by information for patients to help them and their carers understand the available Objective. This discussion document about the techniques and to support treatment choices. management of cancer pain is written from the pain specialists’ perspective in order to provoke thought Methods and interest in a multimodal approach to the manage- ment of cancer pain, not just towards the end of life, This document has been produced by a consensus group but pain at diagnosis, as a consequence of cancer of relevant health care professionals and patients’ repre- therapies, and in cancer survivors. It relates the sentatives making reference to the current body of evi- science of pain to the clinical setting and explains the dence relating to cancer pain. role of psychological, physical, interventional and complementary therapies in cancer pain. Executive Summary

Methods. This document has been produced by a • It is recognized that the World Health Organisation consensus group of relevant healthcare profession- (WHO) analgesic ladder, while providing relief of cancer als in the United Kingdom and patients’ representa- pain toward the end of life for many sufferers world- tives making reference to the current body of wide, may have limitations in the context of longer sur- evidence relating to cancer pain. In the second of vival and increasing disease complexity. To complement two parts, physical, invasive and complementary this, it is suggested that a more comprehensive model cancer pain therapies; treatment in the community; of managing cancer pain is needed that is mechanism- acute, treatment-related and complex cancer pain based and multimodal, using combination therapies are considered. including interventions where appropriate, tailored to the needs of an individual, with the aim to optimize pain Conclusions. It is recognized that the World Health relief with minimization of adverse effects. Organization (WHO) analgesic ladder, whilst provid- • The neurophysiology of cancer pain is complex; it ing relief of cancer pain towards the end of life for involves inflammatory, neuropathic, ischemic, and com- many sufferers world-wide, may have limitations pression mechanisms at multiple sites. Knowledge of in the context of longer survival and increasing these mechanisms and the ability to decide if a pain is disease complexity. To complement this, it is sug- nociceptive, neuropathic, visceral or a combination of all gested that a more comprehensive model of manag- three will lead to best practice in pain management. ing cancer pain is needed that is mechanism-based • People with cancer can report the presence of several and multimodal, using combination therapies inclu- different anatomical sites of pain that may be caused by ding interventions where appropriate, tailored to the the cancer, treatment of cancer, general debility or con- needs of an individual, with the aim to optimize pain current disorders. Accurate and meaningful assess- relief with minimization of adverse effects. ment and reassessment of pain is essential and optimizes pain relief. History, examination, psychosocial Key Words. Cancer Pain; Palliative Treatment assessment and accurate record keeping should be routine, with pain and quality of life measurement tools used where appropriate. • Radiotherapy, chemotherapy, hormones, bisphospho- Preface nates and surgery are all used to treat and palliate cancers. Combining these treatments with pharmaco- This discussion document, which can be more fully logical and nonpharmacological methods of pain accessed at www.britishpainsociety.org/book_cancer_ control can optimize pain relief, but limitations of these pain.pdf, about the management of cancer pain is written treatments have also to be acknowledged. from the pain specialists’ perspective in order to provoke • Opioids remain the mainstay of cancer pain manage- thought and interest in a multimodal approach to the ment, but the long-term consequences of tolerance, management of cancer pain, not just toward the end of dependency, hyperalgesia and suppression of the life, but pain at diagnosis, as a consequence of cancer hypothalamic/pituitary axis should be acknowledged therapies, and in cancer survivors. It relates the science of and managed in both noncancer and cancer pain, as pain to the clinical setting and explains the role of psycho- well as the well known side-effects such as constipation. logical, physical, interventional and complementary thera- NSAIDs, anti-epileptic drugs, tricyclic antidepressants, pies in cancer pain. NMDA antagonists, sodium channel blockers, topical agents and the neuraxial route of drug administration all It is directed at physicians and other health care profes- have a place in the management of complex cancer pain. sionals who treat pain from cancer at any stage of the • Psychological distress increases with intensity of cancer disease and it is hoped that it will raise awareness of the pain. Cancer pain is often under reported and under- types of therapies that may be appropriate, heighten treated for a variety of complex reasons partly due to a appreciation of the role of the pain specialist in cancer pain number of beliefs held by patients, families and health management, and lead to dialogue and liaison between care professionals. There is evidence that cognitive oncology, specialist pain and palliative care professionals. behavioral techniques that address catastrophizing and

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promote self efficacy lead to improved pain manage- • Patient education is an effective strategy to reduce pain ment. Group format pain management programs could intensity. contribute to care of cancer survivors with persistent • Cancer pain is often very complex but the most intrac- pain. table pain is often neuropathic in origin, arising from • Physiotherapists (PTs) and occupational therapists tumor invasion of the meninges, spinal cord and dura, (OTs) have an important role in the management of nerve roots, plexuses and peripheral nerves. Multimodal cancer pain and have specific skills that enable them to therapies are necessary. be patient-focused and holistic. Therapists utilize strat- • The management of cancer pain can and should be egies that aim to improve patient functioning and quality improved by better collaboration between the disci- of life, but the challenge remains to practice in an plines of oncology, pain medicine and palliative medi- evidence-based way and more research is needed in cine. This must start in the training programmes of this field. doctors, but also in established teams in terms of • Patient selection for an interventional procedure funding, time for joint working, and education of all requires knowledge of the disease process, the prog- health care professionals involved with the treatment of nosis, the expectations of patient and family, careful cancer pain. assessment and discussion with the referring physi- • The principles of pain management and palliative care in cians. There is good evidence for the effectiveness of adult practice are relevant to pediatrics, but the adult coeliac plexus neurolysis and intrathecal drug delivery. model cannot be applied directly to children. Within the limitations of running randomized controlled trials (RCTs) for interventional procedures in patients Part 2 of 2: Physical, Invasive and Complementary with limited life expectancy and severe pain, there is a Cancer Pain Therapies; Treatment in the body of evidence of data over many years that supports Community; Acute, Treatment-Related and an important role for some procedures (e.g., cordo- Complex Cancer Pain tomy). Safety, aftercare and management of possible complications have to be considered in the decision Physical Therapies in Cancer Pain making process. Where applied appropriately and care- fully at the right time, these procedures can contribute Summary enhanced pain relief, reduction of medication use and markedly improved quality of life. PTs and OT) have an important role in the management of • There is a weak evidence base for the effectiveness of cancer pain and have specific skills which enable them to complementary therapies in terms of pain control, but be patient-focused and holistic. Therapists utilize strate- they may improve well being. Safety issues are also a gies that aim to improve patient functioning and quality of consideration. life but the challenge remains to practice in an evidence- • Patients with cancer pain spend most of their time in the based way. More research is needed in this field. community until the last month of life. Older patients and those in care homes may particularly have under- Introduction treated pain. Primary care teams supported by palliative care teams are best placed to initiate and manage PT and OT play an important role in the management of cancer pain therapy, but education of patients, carers patients with cancer pain and may encounter these and health care professionals is essential to improve patients at various stages in the “cancer journey.” Reha- outcomes. bilitation of cancer patients is gaining increasing recogni- • Surgery, chemotherapy and radiotherapy are cancer tion and is now considered an essential component in the treatments that can cause persistent pain in cancer delivery of care [1]. survivors, up to 50% of whom may experience persis- tent pain that adversely affects quality of life. Awareness The main aims of therapy are to relieve pain (wherever of this problem may lead to preventative strategies, but, possible) and to improve function and quality of life using at the moment, treatment is symptom based and often treatments based on the best available evidence. Manage- inadequate. ment should be patient-centered, collaborative and restor- • Management of acute pain, especially postoperative ative and involve family and carers to ensure a coordinated pain, in patients on high dose opioids is a challenge approach to treatment planning and goal-setting. The that requires in-depth knowledge of pharmacoki- patient’s engagement in the therapy partnership is vital. netics and formulation of a careful management plan to avoid withdrawal symptoms and inadequate pain Early referral to therapies is important not only with the management. palliative care patients, but also with others, to prevent • Chronic pain after cancer surgery may occur in up to chronicity and help anticipate future problems. With 50% of patients. Risk factors for the development of in-patients, early referral should result in better discharge chronic pain after breast cancer surgery include: young planning that may stop bed blocking and help patients age, chemo and radiotherapy, poor postoperative pain return to their preferred place of care. control and certain surgical factors. Radiotherapy induced neuropathic pain has become less prevalent Much can be learned from therapists who work with mus- but can cause longstanding pain and disability. culoskeletal pain and there is a plethora of literature exam-

874 Cancer Pain Treatments: Part 2 ining the role of physiotherapy and occupational therapy depression). Assessment will focus on a patient’s func- for patients with benign pain. Therapists working with tional ability (e.g., their ability to transfer or mobilize). There cancer patients may find some of these messages helpful are three components of assessment that must be con- but must recognize that the majority of this work has sidered in all patients: a description of the pain (including focused on a noncancer population. site, severity, irritability, nature); responses to the pain and the impact of pain on the person’s life [9]. Assessment Therapists must be aware of the dangers of placing too Impact of Cancer-Related Pain much attention on correction of physical impairments at the expense of function [10]. For many cancer patients Pain can reduce strength, vitality, activity tolerance and (especially those with advanced disease) it will be more mobility [2,3]. Cancer patients with pain report significantly important to complete a task than to focus on correction lower levels of performance status than those without pain of individual impairments. [4,5] demonstrated that pain due to cancer was associ- ated with higher levels of perceived disability and a lower Occupational Therapy Assessment degree of activity. Pain may affect a person’s ability to care for themselves, to work or to participate in fulfilling activi- Occupational therapy assessment recognizes it is usual ties. The experience of cancer pain may also result in for cancer patients to identify and focus on those tasks disruption to family and carers’ quality of life [6]. and occupational roles that they are no longer able to manage or enjoy due to their pain. The OT will listen to the A common response to pain is the development of “pain patient’s narrative and begin to identify aggravating, reliev- behaviors.” This includes maladaptive behaviors such as ing factors; the beliefs held regarding pain; what the pain guarding the painful area, pain watching (hyper-vigilance), means to the patient, those around them; how the patient developing an overly sedentary lifestyle and avoiding is currently managing their activities in relation to their activities. This inactivity can result in deconditioning, pain. increased muscular tension and increased attention to pain. The OT will identify which activities the individual needs to do, wants to do and is expected to do by others. Responses to Cancer-Related Pain Evaluating Outcome It is essential to explore the meaning of pain to the patient and to those closest to them. An individual’s cultural back- It is important to utilize reliable and valid outcome mea- ground, spiritual, religious and philosophical beliefs all sures as well as utilizing patient’s subjective feedback. impact upon perception and response to cancer pain. Outcome measures for use in clinical practice must be feasible (i.e., practical, inexpensive and easy to use), Thoughts and emotional responses can contribute to the provide extra clinical information and be responsive to intensity of the pain experience [7]. Anxiety, depression, changes over time. A great variety of tools are now avail- fear of the future, hopelessness, negative perceptions of able but there are no published guidelines for therapists to personal and social competence, decreased social assist selection of measures. activity/social support and lack of control over pain may all be important [8]. Outcome Measures

Principles of Assessment Both visual analog scales and numerical ratings scales (NRSs) are commonly used in clinical practice. Previous Therapy assessments must include subjective and objec- research has suggested cutoff points for mild, moderate tive evaluation and must utilize all available information and severe pain on a NRS, with 0–4 mild, 5–6 moderate, from medical notes, other members of the MDT and 7–10 severe. This is useful to consider when asses- patients and carers themselves. All relevant comorbidities sing whether improvements in pain report are clinically need to be considered. Assessment is rarely possible over significant. one interaction; it is an information gathering exercise and is a continual process which guides initial and ongoing Example: A drop in pain report from 9/10 to 7/10 may be treatment. Optimal timing of pharmaceutical management less clinically significant than a drop from 7/10 to 5/10, is often required to enable patients to participate fully in although the incremental change is the same. assessment. The brief pain inventory [12] is a useful clinical tool for Physiotherapy Assessment therapists as it reports both pain intensity and pain inter- ference using a NRS. This will require detailed examination of physical factors (e.g., joint range of movement, muscle power, postural It is important that the patient remains at the center of the changes); with recognition of and appropriate manage- treatment process. A measure that can be used to detect ment of psychological comorbidities (e.g., anxiety or the impact of therapy intervention on the patient’s self-

875 Raphael et al. perception of occupational performance is the Canadian Postural Re-education Occupational Performance Measure [13]. It has also been demonstrated to empower and actively encourage patient Postural re-education is appropriate in patients who have participation in therapy interventions. altered posture or movement secondary to pain. It is important to attempt correction of such postural abnor- Other tools that can be used include pain drawings (often malities early in rehabilitation to avoid further dysfunctional simple body charts) or descriptive questionnaires such as movement patterns. Examples include breast cancer the McGill Pain Questionnaire [14]. patients who develop chronic postsurgical pain following breast cancer treatment and adopt protective postures resulting in muscle spasm and muscle imbalances [19]. In Therapy Management head and neck cancer patients, there is growing evidence for the use of Progressive Resistive Exercise training to The ultimate aim is for the patient to achieve full functional manage shoulder dysfunction and pain secondary to potential and become autonomous in managing the spinal accessory nerve damage. The importance of cor- impact of pain on their daily life. There is currently a lack of recting posture and scapular stability prior to resistance evidence for the use of therapy interventions for patients exercise has been documented [20]. with cancer-related pain and research is required in this field. Interventions can be classified as physical, psycho- Massage and Soft Tissue Mobilization social and lifestyle adjustment. Soft tissue mobilization is widely practiced in the manage- ment of pain and includes techniques such as scar Physical Approaches mobilization/massage, myofascial techniques and con- nective tissue massage. A wealth of information is avail- Some of these approaches are traditionally administered able on such approaches [21,22]. by PTs (e.g., therapeutic exercise and transcutaneous electrical nerve stimulation [TENS]) but other health care TENS practitioners (HCPs) may have sufficient skills in this area (e.g., OT, clinical nurse specialists). Graded activity for TENS is a noninvasive form of electrical stimulation that return to function is inextricably linked with therapeutic has been used for many years to treat a wide range of pain exercise but may traditionally be considered the domain of problems. Although experts suggest that TENS has an the OT. When utilizing these approaches, a certain amount important role there are currently no formal guidelines on of manual handling is required and therapists must pay the use of TENS in cancer patients. Only two RCTs evalu- special attention to patient comfort and position at all ating TENS use in cancer-related pain have been identified times. [23,24] and the effectiveness of TENS remains inconclu- sive [25]. Yet some patients may find it beneficial.

Therapeutic Exercise Conventional TENS is the most common mode of delivery used in practice and should be the first treatment option in The main goal of exercise is to address the problems most situations. It is generally recommended to start with associated with inactivity/immobility (specific or general) TENS electrodes in the painful area or an adjacent der- and fear of movement. The detrimental effects of immo- matome. The intensity should be “strong but comfortable” bilization are well documented and include muscle and patients can safely increase treatment time up to wasting/weakness, joint stiffness, reduced motor control, several hours as long as no side-effects occur and benefit mood changes, decreased self-efficacy, reduced coping continues. capacity and cardiovascular deconditioning. Exercise pro- grams must be tailored to the individual needs of the Heat and Cold Therapy patient and should start cautiously, build up gradually and be within patients’ tolerance levels. There are now many Application of heat can be achieved from simple reviews of exercise in cancer patients, some of which approaches (e.g., a hot bath to aid relaxation or more local include guidance on specific precautions [15,16]. applications such as heated packs). Cold can be delivered via ice packs and home remedies can be devised (e.g., using frozen peas, wrapped in a towel or protective fabric Graded and Purposeful Activity to prevent frost burn). All standard contraindications and precautions must be followed and choice of treatment will Engagement in meaningful activities (which may include depend on pain presentation and the therapeutic effects craft, recreation or work) has been shown to assist needed. patients with cancer pain to improve their self-concept and attain task mastery [17]. Appropriately prescribed and Lifestyle Adjustment graded activities, can be used to increase activity toler- ance, autonomy, social integration, self-esteem and com- Typically, it is the OT who addresses this aspect of man- petency, and decrease pain behaviors [18]. agement although the PT can also be involved in some

876 Cancer Pain Treatments: Part 2 aspects (e.g., prescription of walking aids). Analysis of pain, palliative care and nursing. The team might include activity tolerance levels and education in skills can enable others. Practical factors should be considered, such functional restoration without provoking painful episodes. asdischarge home, patient and family preferences. Techniques such as pacing, planning, prioritizing, energy Complex situations will often require high level discussion. management, activity analysis, work simplification, time management, compensatory techniques, ergonomic prin- It has been traditional to consider exhausting oral or ciples, and the reorganization of routines can be taught to topical analgesia before considering invasive methods; provide the patient with skills to restructure their lifestyle, however, this is not always in the patients best interests. thus minimizing painful episodes. Where there are unacceptable side-effects from opioids, such as drowsiness, then invasive methods may be pre- Analyzing, grading and adapting activities allows patients ferred or an implanted pump early in advanced cancer can to continue managing them within their ability, tolerance allow for the maximum benefit to be obtained. level and pain parameters [26,27]. The restructure of lif- estyle and routine, environmental adaptation, task simpli- This chapter aims to bring information related to benefits fication, fatigue management, appropriate equipment and and adverse effects for interventional procedures com- orthotic prescription and interventions regarding correct monly used in cancer pain management. positioning and pressure relief during activity facilitate independence, conserve energy, minimize pain on exer- tion and enable valued activities to be continued. Types of Interventional Procedures

Invasive Procedures in Cancer Pain These most typically involve interruption to or modification of nerve conduction with the aim of diminishing pain from Summary a target area. The nerves involved include those of the peripheral, autonomic and central nervous system. Patient selection for an interventional procedure requires knowledge of the disease process, the prognosis, the The procedures may be considered as nondestructive or expectations of patient and family, careful assessment and destructive. In nondestructive procedures, nerve blockade discussion with the referring physicians. There is good or modulation is achieved by the deposition of reversible evidence for the effectiveness of coeliac plexus block and pharmacological agents. These may be provided by bolus intrathecal drug delivery. Safety, aftercare and manage- injection and most commonly involve local anesthetic ment of possible complications have to be considered in agents often supplemented by depot steroids. Alternatively the decision making process. Where applied appropriately catheter placement allows for the continuous delivery of and carefully at the right time, these procedures can con- agents. When placement is adjacent to peripheral or auto- tribute enhanced pain relief, reduction of medication use nomic nerves similar agents are used. For catheter place- and markedly improved quality of life. ment in the spinal canal with the aim of modulating neuronal activity of the spinal cord, different agents are used. These Introduction are most commonly opioids often supplemented by local anesthetics and/or the alpha-2 adrenergic agonist, cloni- This chapter focuses on the interventional procedures dine. More recently, the voltage gated calcium channel considered the most effective. It deals with the pharma- blocker, ziconotide has been introduced [28]. cological blockade of neural tissue by targeted injection or infusion, their destruction by chemical, physical or sur- The destructive procedures involve the use of chemical gical methods and the fixation of vertebral compression agents (alcohol 50–100% and phenol 6–10%), physical fractures. methods of heat (radiofrequency) and cold (cryoablation) and surgery. For a few procedures (coeliac plexus ablation, intrathecal infusions, see below) there is controlled trial evidence in Destructive procedures must only be provided by appro- cancer populations. For most procedures there is less priately trained personnel, and are best offered within a robust evidence of largely uncontrolled case series. multidisciplinary framework of care recognizing the psy- chosocial components of pain experience. Failure to do so A pragmatic approach is required when deciding whether is likely to reduce the efficacy of such procedures. to offer such therapies. The likely benefits and possible risks need to be considered and compared with those of Patients should be thoroughly informed about likely continuing with pharmacological management. Typically, sensory deficits and possible complications. In most interventional management of cancer pain does not sub- cases, destructive procedures should first be simulated stitute for other modalities but can improve pain relief and with local anesthetic to allow the patient to experience the allow for a reduction in systemic medications and their sensory changes that may occur [29]. side-effects. The patient should be closely followed as an inpatient for Careful assessment of the pain should be undertaken by several days after the destructive procedure with close an interdisciplinary team usually including specialists in monitoring and planned opioid reduction to avoid drowsi-

877 Raphael et al. ness and respiratory depression when the respiratory pharmacological management together with sham proce- stimulation of pain is removed. dure. Pain relief was better in the interventional group for 6 weeks [46]. A meta-analysis [47] of five RCTs of coeliac Peripheral Nerve Blockade plexus ablation, found significantly improved pain relief when compared with pharmacological management or Peripheral nerve blocks have a limited role in cancer pain local blockade of the plexus for 8 weeks with reduced management. There is no controlled trial evidence but opioid consumption in the ablation group. case series describe pain relief for a short time with local anesthetic blockade of the regional nerve supply of a Up to 30% of patients experience hypotension after coeliac target area. They may therefore be useful for perioperative plexus block due to loss of sympathetic tone and splanch- pain, and other acute cancer pains such as pathological nic vasodilatation [48]. This reaction usually manifests itself rib fracture (intercostal nerve blockade). This may be within the first 12 hours. Up to 60% of patients report achieved by bolus injection of local anesthetic. It is often diarrhoea due to sympathetic blockade and unopposed supplemented with depot steroid with the aim of providing parasympathetic efferent influence after coeliac plexus longer term relief but there is no evidence to support this block, which usually resolves within 48 hours [49]. Neuro- for peripheral nerves [30]. Alternatively, catheter infusions logic complications, including paraplegia, leg weakness, of local anesthetic adjacent to brachial plexus [31] or other sensory deficits, and paresthesias, have been reported nerves may prolong the pain relief [32,33]. after coeliac plexus ablation and with a large study report- ing four cases of paraplegia after 2,730 coeliac plexus Neurolytic blockade of peripheral nerves produces short- blocks [50]. Paraplegia was attributed to either direct injury term relief, for example, intercostal neurolysis has a of the spinal cord during the procedure or spinal infarction median duration of 3 weeks [34]. Although this study secondary to spasm of the spinal artery. found no incidences of neuritis, the survival time was short, and others have reported an incidence of neuritis of Theoretically, radiofrequency splanchnic denervation 30% [35]. Neurolytic agents should be limited to those should avoid the risk of such paraplegia [51] but outcome with short life expectancy. is less studied. It may be an option when relative risks are discussed with the patient. Autonomic Nerve Blockade

It is known that the sympathetic nervous system carries Superior Hypogastric Plexus Block pain afferents from the viscera and that blockade can reduce pain. The superior hypogastric plexus carries afferent from the bladder, uterus, vagina, prostate, testes, urethra, Coeliac Plexus Ablation descending colon and rectum. Superior hypogastric block may relieve pelvic pain and a block of these nerves has The coeliac plexus carries visceral afferents from several been described to reduce pain associated with pelvic abdominal organs including the pancreas, liver, biliary malignancy [52]. Posterior approach is commonest but an tract, renal pelvis, ureter, spleen, and bowel up to the first anterior approach has been described [53]. part of the transverse colon. Ganglion Impar Block Injection of a neurolytic medication around the coeliac plexus has been most investigated for pancreatic cancer This is the most inferior sympathetic ganglion lying anterior pain but has found a role for other upper gastrointestinal to the sacrococcygeal junction. It has been shown in case malignancies such as gastric cancer, esophageal cancer, series to provide pain relief for patients with advanced colorectal cancer, liver metastasis, gallbladder cancer and cancers of the pelvis and perineum, after abdomino- cholangiocarcinoma [36]. perineal resection for rectal cancer [52] and following radiation proctitis [54]. Access to the plexus is most commonly posterior with needle placement in front of or posterior to the crura of the diaphragm [37], but other approaches are used such as Neuraxial Blocks anterior [38], endosopic [39] and transdiscal [40]. Imaging most commonly involves fluoroscopy but alternatives used Neuraxial blocks may be epidural (outside the theca or include computerized tomography [41] and MRI [42]. While dura mater) or intrathecal (into the cerebrospinal fluid). there is no apparent difference in outcome between these methods, they do allow for access in certain individuals Epidural local anesthetic and steroid can provide tempo- where fibrous infiltration or tumor invasion may distort the rary pain relief where a vertebral metastasis is associated anatomy affecting neurolytic spread [43,44] or may be with nerve compression. valuable when patients cannot lie on their front [45]. Care should be exercised if impending cord compression In a single-blind RCT of 100 patients with pancreatic or invasion of the epidural canal by tumor is suspected cancer, neurolytic plexus ablation was compared with and imaging may be advisable in such circumstances.

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Despite the lack of evidence to support these interven- placebo controlled study of Zicomotide in ill patients, 50% tions, several experienced practitioners have and continue on active therapy vs 17% on placebo achieved >30% pain to use these techniques with reported benefit to patients. relief. However, 30% on ziconotide vs 10% on placebo Epidurals with steroid and local anesthetic can provide experienced “serious” side-effects, 38% of those on temporary pain relief. ziconotide discontinued treatment, and follow-up gener- ally thought to be too short. Fuller details of the use of Intrathecal and Spinal Nerve Root Neurolysis intrathecal therapies is found elsewhere [61].

A saddle block with heavy intrathecal phenol can be used Intraventricular opioids can be administered via an for perineal pain of somatic origin in advanced pelvic implanted pump and catheter for pain in the head and face. cancers, especially where bladder and bowel function are Cerebrospinal fluid diversion via a shunt or third ventricu- already compromised. lostomy may be appropriate for palliation in some cases of obstructive hydrocephalus that are otherwise inoperable; Chemical neurolysis of spinal nerve roots is used less craniotomy and subtotal removal of a malignant cerebral frequently than in the past as safer interventions (e.g., tumor is a routine neurosurgical palliative procedure. neuraxial infusions have been developed). While there are case series describing effective relief of pain, the duration Domiciliary Management of Spinal Catheters is limited and the incidence of neurological deficits is high [55]. Most patients want to die at home [64], and while the safe management of spinal drug infusions does present chal- Neuraxial Infusions lenges to this, these can be overcome to facilitate this aim [65]. In addition, with percutaneous drug delivery, intrath- Some patients with advanced cancer may have pain that ecal use allows lower dose and therefore longer intervals cannot be controlled with systemic medications, or the between infusion refilling of ambulatory pumps, facilitating use of these medications may be limited by unacceptable home care and reducing the risk of infection. Intrathecal side-effects at doses below those required to give catheters may be less prone to dislodgement, and block- adequate relief. For these patients administration of drugs age due to fibrosis [66], and have been shown to be safer by the spinal route, either epidurally or intrathecally, may in the domiciliary setting [67]. be required and gives good control in the majority of cases [56]. Preparation

There are different types of procedures ranging from per- Full involvement of the primary care team in the manage- cutaneous lines to fully implanted programmable pumps. ment of pain is vital. If, when considering the use of spinal The fully implanted systems carry less risk of infection and drug delivery, management at home is identified as a have lower maintenance but the operation is more pro- priority it is essential to establish that the patient and family longed [57]. Costs of the therapy currently suggest are suitable and have appropriate goals and expectations. implanted systems are more cost effective than the per- The community nursing and primary care teams should be cutaneous after 3 months [58]. happy to cooperate and be involved.

There is evidence from RCTs of improved pain relief and Psychological assessment should be considered once less drug related side-effects compared with medical pain has been relieved, and sedation due to analgesics therapy for fully implanted systems. The reversal of minimized, some patients may be less distracted from the drowsiness associated with systemic opioids is of great other psychological aspects of their illness. This can lead practical significance [28,59,60]. to difficulties with good symptom control. Full discussion and consent from the patient and family, taking factors These procedures carry a moderate level of minor adverse such as these into consideration, is essential. effects and a low level of serious adverse effects [57]. They should be reserved for those patients whose pain cannot Procedure be controlled with systemic analgesia and undertaken in centers experienced with the technique and its aftercare Percutaneous catheters, injection portals or fully implanted [61]. systems may be used, but a factor in patient selection is the shorter expectation of survival in this group compared with The most effective drugs are opioids, commonly mor- patients with nonmalignant pain. Percutaneous catheters phine, and generally patients who respond to spinal mor- may be tunnelled or nontunnelled: tunnelled catheters are phine are those who respond to systemic morphine but less prone to displacement and infection [56]. only partially and/or are limited by dose related side- effects. Patients who are unresponsive to large doses of Implantation and other procedures are ideally done in a systemic opiods are unlikely to respond to spinal opioids. sterile facility with resuscitation facilities in a hospital or Other drugs that appear to be effective spinally include hospice. Insertion as a domiciliary procedure has been local anesthetics (typically bupivacaine) [62], alpha-2 ago- reported [68], but this does raise issues with sterility and nists (clonidine) [63] and ziconotide [28]. In a randomized the ability to resuscitate in the event of side-effects.

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Very compact and reliable battery-powered infusion closely tied to the hospital/hospice allowing greater pumps are available that allow both continuous and freedom and independence that was dramatic in some patient-controlled bolus drug administration. cases (e.g., holidays abroad). There were no new sphinc- ter disturbances reported. Aftercare Midline Myelotomy It is imperative that those who will be involved in the patient’s management at home are fully trained and con- Splitting the spinal cord in the midline posteriorly was fident in the necessary techniques and knowledge before intended to divide the spinothalamic fibers as they discharge. The patient’s management should also be sta- crossed, thereby controlling bilateral pain while avoiding bilized as an inpatient or in hospice prior to discharge the risks of bilateral cordotomy. Introduced in 1926, it was home, with titration down of systemic analgesics, in par- not particularly successful until the serendipitous observa- ticular to avoid opioid overdosage [69]. The cooperation of tion in 1970 that a single level myelotomy at C1 produced the patient’s general practitioner and out of hours service analgesia over a wide body area. It was subsequently is important, and this is supported by the availability of found that a limited midline myelotomy at T10 was effec- detailed guidelines or protocols, and back-up from tive against pelvic visceral cancer pain [73]. The recent members of the specialist pain or palliative care team is discovery of a specific pathway in the medial dorsal essential [61]. This should be recognized in job plans. columns which conducts visceral pain [74] provides a possible substrate for this operation that appears to be With appropriate training and compliance with competen- very effective and safe [75] but is rarely used. cies, refilling of infusion reservoirs can be performed by community nursing staff, as well as monitoring of the patient’s condition: particularly pain relief, temperature Other Neurosurgical Procedures and the state of implantation sites. Again, guidelines or protocols should support this. In the past, many surgical targets in the brain have been tried with varying degrees of success and morbidity, but Anterolateral Cordotomy none is now used more than sporadically. This includes sites in the medulla, pons, midbrain, thalamus and hypo- This can be undertaken as a percutaneous or open pro- thalamus, and the somatosensory and cingulate cortices. cedure involving intervention on the side of the spinal cord The pituitary gland provided one of the most useful targets; opposite to that of the pain to ablate the spinothalamic transnasal alcohol-induced hypophysectomy was very tract fibers. Consequently, it reduces the sensation of effective against hormone-dependant and diffuse cancer touch and temperature in addition to pain. pain particularly when due to bone metastases from breast and prostate. Diabetes insipidus occurred in half the The awake percutaneous procedure ablates the spinotha- patients and visual disturbances were common; pharma- lamic tract using radiofrequency lesioning through a needle cological hormonal manipulation has made it redundant. inserted between the first and second cervical vertebrae. Dorsal root entry zone lesions are rarely used for cancer Its value in mesothelioma is well documented [70] and its pain; an extensive laminectomy is required, the morbidity is use in other lateralized pains is recognized [71]. relatively high, only paroxysmal pain responds well and cordotomy or rhizotomy are likely to be preferable. Immediate pain relief is achieved in the majority with 80% either stopping or reducing opioids but pain recurs in a third Vertebroplasty of these by 6–12 months [70]. The main risk is of weakness of the leg contralateral to the side of the pain through Painful pathological fractures of vertebra that do not damage to the corticospinal tract, mild effects are seen in respond to the conservative therapies of medications, up to 8–10% in the first few days, but prolonged effects are TENS, steroid epidurals can be considered for fixation by reported in 1–2% [71]. This risk increases, for topographi- cemented vertebroplasty. Open studies in myeloma and cal reasons, when the lower sacral dermatomes are tar- metaststic cancers report pain relief that is often complete geted. Painful dysethesias occur in about 5% [70]. in around 80% of patients [76–78]. Cement leak is the commonest risk at around 5%; however, complications Whereas percutaneous cordotomy can only be performed from this are rare but are serious [79]. in the cervical area, the spinothalamic fibers can be divided by open operation in the thoracic cord. This avoids the risk to respiration and to the upper limb when the pain Complementary Therapies in Cancer Pain is below the waist (e.g., secondary to invasion of the lumbosacral plexus and is recommended for bilateral pro- Summary cedures to avoid fatal sleep apnoea). In a small series [72], none of the patients experienced motor weakness and all There is a weak evidence base for the effectiveness had complete or nearly complete and sustained relief of of complementary therapies in terms of pain control, but the target pain, allowing a substantial reduction in medi- they may improve well being. Safety issues are also a cation for all but one. This released them from being consideration.

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Introduction A systematic review of six RCTs found no convincing evidence that homeopathic remedies have analgesic Complementary and alternative medicine (CAM) refers to effects in cancer patients [86]. a diverse array of treatment modalities and diagnostic techniques. It has been defined as “diagnosis, treatment Hypnotherapy and/or prevention which complements mainstream medi- cine by contributing to a common whole, satisfying a This is the induction of a trance-like state to facilitate demand not met by orthodoxy, or diversifying the concep- relaxation and enhance suggestibility for treating condi- tual framework of medicine” [80]. tions and introduce behavioral changes.

Large proportions of cancer pain patients are using CAM Studies have suggested the usefulness of hypnotherapy in [81]. Reasons include dissatisfaction with conventional palliative cancer care. A systematic review found encour- medicine, desperation, compatibility between the philoso- aging evidence that hypnotherapy can alleviate cancer phy of CAM and patients’ own beliefs, and the wish for pain [87]. Due to the often poor methodology of the more control over one’s own health [82]. primary data, this evidence was deemed inconclusive. Similar conclusions were reached in two systematic CAM therapies have the potential to increase well-being reviews for procedural pain in pediatric cancer patients and thus influence pain. They are often employed in addi- [88,89]. tion to conventional treatments in palliative and supportive cancer care. Massage

Acupuncture This is the manipulation of the bodies soft tissue using various manual techniques and applying pressure and This is the insertion of needles into the skin and underlying traction. tissues for therapeutic or preventive purposes at specific sites, known as acupuncture points. Massage seems to increase well-being through reduction of stress and anxiety levels and thus may contribute to A systematic review identified two RCTs and found no pain control. The evidence for analgesic effects in cancer compelling evidence of acupuncture to control cancer patients is encouraging but not convincing [90]. pain [83] that was confirmed by other reviewers. Subse- quent RCTs did not produce convincing evidence of effec- Music Therapy tiveness. It is effective in alleviating chemotherapy-related nausea and vomiting and may hence contribute to pain The use of receptive (passive) and/or active music therapy control [84]. most commonly based on psychoanalytical, humanistic, cognitive behavioral or developmental theory. Aromatherapy There is no convincing evidence from RCT data to Controlled use of plant essences, applied either to the skin suggest effectiveness for pain control in cancer patients through massage, added to baths or inhaled with steam- [80]. ing water. Reflexology A Cochrane systematic review concluded that aroma- therapy and/or massage has beneficial short-term effects The use of manual pressure applied to specific areas, or on well-being in cancer patients [85]. It has, however, not zones, of the feet (and sometimes the hands or ears) that been convincingly demonstrated whether it is associated are believed to correspond to other body areas or organs. with clinically relevant analgesic effects. A few small RCTs generated no convincing evidence that reflexology improves quality of life or pain of cancer Herbal Medicine patients [91]. Medical use of preparations, which contain exclusively Relaxation plant material. There is no convincing evidence for any herbal medicine to suggest effectiveness for treating Techniques for eliciting the relaxation response of the cancer pain [80]. autonomic nervous system resulting in the normalizing of blood supply to the muscles, decrease in oxygen con- Homeopathy sumption, heart rate, respiration and skeletal muscle activ- ity. Most commonly progressive muscle relaxation is used. This is where diluted preparations of substances whose effects when administered to healthy subjects correspond Relaxation techniques have the potential to increase well- to symptoms and clinical signs of the disorder in patients. being and thus may contribute to controlling pain.

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Whether these techniques have direct analgesic effects fore cancer pain management, for patients in the remains, however, unknown. community. Hospice patients consistently rate pain man- agement as a top research priority within palliative care Supplements above other symptoms and aspects of care [93]. An understanding of cancer pain management in the com- Oral medical use of preparations of herbal or nonherbal munity is therefore important for planning services and origin. interventions.

A systematic review of nine RCTs that tested cannabinoids Epidemiology of Cancer Pain in the Community concluded that they are not superior to codeine in con- trolling cancer pain. As cannabinoids cause central Prevalence nervous depression their introduction into routine care was deemed undesirable [92]. Systematic reviews [94,95] have demonstrated that cancer pain is common and its prevalence is related to the Safety Issues stage of illness: 48% of patients with early disease; 59% undergoing cancer treatment; 64–74% with advanced Complementary therapies are often used because they disease. These findings are in keeping with those in the are erroneously considered safe and harmless, which can recent European Pain in Cancer (EPIC) survey of 11 Euro- be dangerously misleading. Some treatments like home- pean countries, which indicated an overall pain prevalence opathy, massage, music therapy, reflexology and relax- of 72% of patients with cancer in the community. This was ation are associated with only mild and rare direct risks if slightly higher in the United Kingdom at 77% [96]. administered appropriately by a trained practitioner. Others have been associated with potentially serious risks: herbal medicines and supplements with herb-drug inter- Pain Severity actions, toxicity and contamination, acupuncture with pneumothorax, hypnosis with negative physiological and Most research on cancer pain severity has been con- psychological effects. General safety issues include mis- ducted in secondary care settings [97,98]. Using a 0–10 diagnosis, or delayed access to effective treatments. Self- numerical rating scale, hospitalized cancer patients typi- medication is another problem due to the potential cally report mean scores for worst pain 4.8, mean score interactions with conventional cancer treatments. Also, for average pain 3.7, worse pain intensity greater than 5 in patients often do not disclose their use of complementary two thirds of patients. medicines to their health care provider who needs to seek the relevant information. There has been less research in community based patients with cancer pain. The EPIC survey invited patients Cancer Pain Management in the Community with cancer pain in the community to participate that were specifically not recruited through palliative care or pain Summary services [96]. For the 617 patients from the UK, the mean pain intensity was 6.4 (identical to the European average); Patients with cancer pain spend most of their time in the over 90% rated their pain greater than 5 out of 10; a community until the last month of life. Overall cancer pain quarter were not receiving any analgesia. prevalence in the community in Europe is 72%. Older patients and those in care homes may particularly have This survey suggests that community based patients have undertreated pain. Primary care teams supported by pal- greater, not less, pain intensity than those in secondary liative care teams are best placed to initiate and manage care and highlights the need for effective strategies in cancer pain therapy, but education of patients, carers primary care. and health care professionals is essential to improve outcomes. Effects of Age on Pain and Treatment

Introduction Concerns exist that older people with cancer experience less effective pain management than younger people Managing patients with cancer pain in secondary or ter- [99–101]. Recent research suggests that when older tiary care settings has several advantages compared with people with cancer are compared with a younger group management in community settings (defined as the there is no significant difference in pain intensity [98,102– patient’s home, care-homes or hospices). These advan- 105]; older people with cognitive impairment report tages include more comprehensive assessment and greater intensity of cancer pain than those without [106]; observation, better access to investigations, and more older people are less likely to receive adequate analgesia direct influence on prescribing and administration of than younger people [107,108] but importantly, these therapy. studies only compared the category of the analgesic pre- scribed for a given pain intensity, and not on the basis of Increasingly however, patient’s wishes and U.K. govern- whether the analgesic therapy was effective in reducing ment policy advocates improved palliative care, and there- pain.

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Further research into the differences in analgesic prescrib- Role of Carers ing between older and younger people has shown that older people generally require lower doses of analgesia, Carers and family members are important sources of especially opioids, than younger people even when con- support for patients with cancer pain. However, carers can trolling for pain intensity [102–104,109]. This may be due have a powerful influence on the management of pain in to a physiological phenomenon, for example, impaired an individual patient. Carers’ barriers are often similar in analgesic metabolism and excretion. Older people may nature to patient barriers but also include hesitancy to sometimes need higher doses; 58 older people aged over administer analgesia. Ethnicity of carers may also influ- 75 years attending a German pain clinic received higher ence BQ scores. doses of opioids than those aged under 65 years [110]. Older people do not experience more adverse effects, High scores by carers on the Barriers Questionnaire have dose escalation or the need for opioid switching, than been shown to more strongly predict inadequate cancer younger people [103,110]. Older people may have poorer pain management than patient scores (based on patient attitudes and knowledge about pain and analgesia than pain scores and level of analgesia); be associated with younger people and therefore, are reluctant to have stron- reports from carers that a patient’s pain is uncontrolled ger analgesia [111,112]. [119,120].

In summary, age does not appear to impact upon pain Health Care Professionals intensity, but older age does appear to be associated with lower doses or potency of analgesic therapy in secondary Knowledge and attitudes of health care professionals care settings. These settings include hospital or hospice toward cancer pain management vary. When these have inpatient units and out-patient clinics. There is a paucity of been compared directly [121,122] nurses have been research on community based patients with cancer pain. shown to have better pain assessment skills than doctors or pharmacists; doctors had better knowledge about clini- cal therapy; pharmacists had most knowledge about Time Spent by Patients in the Community opioid pharmacology; all three professional groups scored poorly in some area. Patients with cancer pain spend most of their time in the community. RCTs from Italy and Norway that have exam- These comparisons demonstrate the need for clinical ined the impact of home-based palliative care teams have teams rather than individuals to be involved in managing shown that in the last 6 months of life patients referred to cancer pain. such teams spend between 65 and 81% of time at home compared with 65–70% of time in a control group; less Place of Care time was spent at home and more time in hospital in the last month of life [113,114]. Primary care or community settings include care homes (nursing or residential) and patients with cancer pain in this Primary care teams supported by home-based palliative context can sometimes be at a disadvantage. There is a care teams are therefore usually best placed to initiate and high prevalence of daily pain in nursing home residents manage cancer pain therapy for the majority of patients. with cancer and this is often untreated, particularly in older patients [108]. Nursing homes can vary in their level of Barriers to Pain Management staffing and equipment (e.g., syringe drivers) necessary for effective cancer pain management particularly at the very Patient Based Barriers end of life.

Attitudes or behaviors that prevent successful pain man- Access to Opioids agement are referred to as barriers and can be assessed using the Barriers Questionnaire (BQ) [115,116]. Research Opioids are central to effective cancer pain management suggests that the most important of these barriers are fear but access to opioids in the community may be an addi- of consequences of analgesic use (addiction and toler- tional barrier faced by patients. In the United States, phar- ance), fatalism about pain, inadequate communication macies in predominantly ethnic minority areas are with health care professionals, some religious and cultural significantly less likely to carry sufficient opioids than in beliefs may also impede effective pain control [117,118]. other areas [123,124]. There is no comparative data spe- cific to the UK. However, a U.K. study [112] which interviewed older and younger patients with cancer pain at home highlighted Patient-Based Educational Interventions that knowing when to take and titrate analgesia was the most important barrier for all ages; older people found Types of Interventions taking and titrating analgesia significantly more of a barrier than younger people; fear of adverse effects was an Interventions designed to improve knowledge and atti- important barrier for both groups; fatalism and communi- tudes toward cancer pain and analgesia have been cation issues where of less importance. studied extensively. These have been a combination of a

883 Raphael et al. brief coaching session (20–40 minutes) in which patient or Risk Factors for Development of CIPN carer barriers are indentified and addressed, with advice on using analgesia; supported by written material and Longer duration of therapy; high cumulative dose; type of occasionally audiovisual material that patients and carers chemotherapeutic agent (e.g., vincristine, cisplatin, pacli- can review at home. Some studies have examined more taxel); pre-existing neuropathy (including CIPN). intensive interventions that consist of repeated coaching and support by a nurse or researcher. Comparators in Common Features of CIPN these randomized trials have included either usual care or a placebo such as a booklet on nutrition. Symmetrical symptoms; length dependency: “stocking- glove” distribution, distal limb long nerves affected; signs and symptoms of neurosensory dysfunction; onset related Evidence of Effectiveness to administration of neurotoxic therapy: rapid, or delayed or even after therapy has finished; relative sparing of motor A recent meta-analysis of 21 clinical trials [125] has shown function [129]. that educational interventions for community patients with cancer pain significantly improve knowledge and attitudes In addition to interference with microtubular mediated toward pain and analgesia, and reduce pain intensity. axonal transport and anatomical damage, alterations in Compared with control, educational interventions resulted nerve function mediated by pro-inflammatory cytokines, in a mean reduction of around 1 point on a 0–10 numerical immune cells and mitochondria have been postulated as rating scale for both worst and average pain intensity; important in CIPN [130,131]. Pain is not synonymous with produced a similar effect to that seen when adding parac- neuropathy but is associated with higher grades of periph- etamol or gabapentin to patients already treated with eral neuropathy. opioids [126,127]. Assessment Patient and carer education is therefore an important, though probably under-used, component of successful Several assessment tools have been used and validated cancer pain management. [132]. Many are clinician rather than patient based and do not all include assessment of pain, function and quality of Pain Related to Cancer Treatments life. A specific CIPN pain scale could reduce under- reporting and therefore undertreating of CIPN pain. Summary Quantitative sensory testing (QST) does not always reflect Chemotherapy, surgery and radiotherapy are cancer treat- symptoms or correlate with chemotherapy dose nor does ments that can cause persistent pain in cancer survivors, it identify neuropathy earlier than clinical history and up to 50% of whom may experience persistent pain that examination [129]. However, QST is an objective assess- adversely affects quality of life. Awareness of this problem ment that is useful for surveillance of recovery (Table 1). may lead to preventative strategies, but at the moment, treatment is symptom based and often inadequate. Prevention and Treatment

Modification and refinement of chemotherapy dosage Introduction schedules (especially in palliative setting) can reduce CIPN. Specific preventative treatments such as amifos- Chemotherapy, surgery and radiotherapy are cancer treat- tine, glutathione, N acetyl carnitine, N acetyl cysteine, ments that can cause persistent pain in cancer survivor glutamine/glutamate have been studied in humans and patients and adversely affect quality of life and function. animal models with variable success. Vitamin E can reduce cisplatin and paclitaxel induced neuropathy Up to 50% of cancer survivors may experience chronic [136,137]. More research is needed to ascertain effective pain secondary to treatment yet this is under recognized agents without appreciable side-effects or affecting anti- and under reported [128]. Pain in cancer survivors has an cancer efficacy. additional burden in that it is often perceived to be indica- tive of disease recurrence. Supportive education and nonpharmacological treat- ments are important. Simple strategies to reduce the Painful Chemotherapy-Induced Peripheral impact of numb and painful hands and feet, such as Neuropathy (CIPN) reducing water temperature, using aids to help holding cups and utensils, are important. Psychological support, Neurotoxicity is a dose limiting side-effect of many che- physiotherapy and occupational therapies are part of a motherapies and biological therapies (also known as bio- multidisciplinary approach. logical response modifiers that modulate the natural response to tumor cells) used in the treatment of cancer. There is few data on effective pharmacological treat- Peripheral neuropathy is the most prevalent form of ments of CIPN. Current management is predominantly neurotoxicity. based 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, current neuropathic pain treatment guidelines may be used [140– 142]. However, mechanisms of CIPN may be different to other neuropathic pain and more research is needed.

Post Cancer Surgical Pain

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

Post Breast Cancer Surgery Pain (PBCSP) docetaxel less CIPN starting bortezomib CIPN More CIPN with more frequent dosing; Paresthesias common, vinblastine less Carboplatin less CIPN Chronic pain following surgery for breast cancer has been reported with an incidence of over 50%. Similar to other pain in cancer survivors, it is under reported, under rec- ognized and undertreated. Classification is varied and potentially confusing, yet PBCSP is likely to be predomi- nantly neuropathic in origin, secondary to surgical damage. Pain can occur in the scar, arm, chest wall or the breast and is commonly associated with sensory distur- bance. Pain often interferes with function and quality of life.

Risk Factors. Various risk factors predicting the develop- ment of PBCSP have been suggested, although data are conflicting: young age (although may be linked with more 25% no recovery [134] recovery into years months/years aggressive disease and treatment), previous chemo- Acute: Chronic: as cisplatin Acute pain in up to 90%, cold induced therapy and radiotherapy, poorly controlled post operative pain, pre-existing anxiety and depression and surgical ) Some recovery 1–3 months, longer

+ factors. ) + ) @6/12 19% complete recovery, ) Some resolution in 80% over + Surgical Factors. Damage and dysfunction of the intercos- + ) Recovery less likely [135] No cumulative dose response, daily dose

+ tobrachial nerve has been proposed as the main mecha- nism for PBSCP. Some studies showed lower incidence of pain after preservation of the nerve. Thirty per cent still

c. 1 month ( develop pain after preservation, and 30% do not develop Acute: hours Chronic: Onset Time (Coasting) Duration/Recovery Other Differences PBCSP after the nerve is cut. Pain is less common after sentinel node biopsy compared with axillary dissection [143].

Surgical factors are influenced by their impact on post operative pain. Certain studies found that breast conserv- ing surgery led to less chronic pain than more radical surgery, but others have suggested the opposite [144,145]. chronic Chronic (35%) At 2 years 71% some recovery High incidence of neuropathy before Chronic Within days ( Chronic (30% severe) Peak 2–3 weeks ( Type of Neuropathy (Incidence) Reconstructive surgery may be an additional risk factor; however, few studies have examined the more contem- poraneous free flap techniques such as the deep inferior epigastric perforator flaps. Postoperative pain following DIEP flap is less than after latissimus dorsi flap and there- fore putatively associated with less chronic pain. Neuropathies associated with specific chemotherapies and biological therapies Treatment and Prevention. Reduction of risk factors for the chemotherapy-induced peripheral neuropathy.

= development of PBSCP such as attention to good post [135] [129] (vinblastine) operative pain control, careful choice of surgical proce- Bortezomib (Velcade®) Thalidomide Chronic Any time ( Paclitaxel (docetaxel) Vincristine [132] Oxaliplatin [133] Acute (90%) and Table 1 Chemotherapy Cisplatin (carboplatin) Chronic c. 1 month ( CIPN dure and meticulous technique could reduce PBSCP.

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A few small trials of treatments for PBSCP have demon- thectomy have been used, but evidence is limited. Current strated modest and variable benefits from capsaicin and therapies are also based upon existing treatments for EMLA cream, gabapentin, amitriptyline and venlafaxine. other neuropathic pain. Nevertheless, treatment includes best practice for general neuropathic pain management in a multidisciplinary Pelvic Pain after Radiotherapy approach. Radiotherapy for pelvis malignancy can also lead to Post Thoracotomy Pain radiation-induced chronic pain syndromes. Pain results from multiple mechanisms, including effects on gut, Persistent pain following thoracotomy for malignant and nerves and pelvic and hip fractures. Dysuria may occur in nonmalignant indication may occur in more than 50% of 20% of patients 1 year after pelvic radiation [128]. In one patients [146] and as for other types of chronic postop- study, nearly 50% of patients reported pain in back and erative pain may be related to perioperative nerve damage lower extremities which was poorly controlled with anal- [147]. Similarly, postoperative pain is a risk factor for gesics and had a negative influence on quality of life [152]. chronic pain. Video-assisted thoracoscopic lung surgery Treatment is symptom-based although, as for BPN, pre- (VATS) is associated with a lower incidence of persistent ventative strategies are being explored. pain. Management of Acute Pain in Cancer Patients Post Head and Neck Surgery Pain Summary Surgery, in addition to chemotherapy and radiotherapy, is Management of acute pain, especially postoperative pain, associated with chronic long-term pain for patients with in patients on high dose opioids is a challenge that head and neck cancer. Pain can occur in the oral cavity, requires in depth knowledge of pharmacokinetics and face neck or shoulder. The incidence of chronic pain after formulation of a careful management plan to avoid with- surgery is similar to other post cancer surgery pain, about drawal symptoms and inadequate pain management. 40% at 1 year and 15% at 5 years [128]. Of the 33% of patients who had pain 1 year after neck dissection, most Introduction had features of neuropathic pain [148]. Treatment depends on careful assessment, providing information to Patients with cancer who present for surgery on high dose patients and a combination of physical and pharmacologi- opioids are a heterogeneous group with a number of cal approaches. complex perioperative analgesic management problems. The main issues include: physical dependence and the Radiotherapy Induced Pain precipitation of withdrawal symptoms if insufficient post- operative opioid is prescribed, and tolerance to the effect Radiotherapy is used as a primary adjunctive treatment for of postoperative opioids. Additionally there may be diffi- many types of cancer. Certain tissue such as skin, culties in calculating dosage conversions between differ- mucous membranes and nerves, are more susceptible to ent types of opioid and different routes of administration. damage. Tolerance Radiation-Induced Brachial Plexus Neuropathy (BPN) Tolerance is a phenomenon in which exposure to a drug Radiation-induced BPN was associated with breast con- results in the diminution of an effect or the need for a servation strategies and deep delivery of radiotherapy in higher dose to maintain an effect. It may develop 1–2 the 1960s and 1970s. Modification of radiotherapy treat- weeks or more after initiation of opioid therapy. A larger ments have reduced the incidence of BPN [149,150]. BPN dosage of opioid will be required to achieve the desired usually occurs at least 6 months after therapy, although effect. Short-acting opioids should be titrated to effect in a higher doses may have a reduced latency. The major controlled, monitored environment. differential diagnosis is tumor related plexopathy. In addi- tion to clinical factors, MRI may aid diagnosis. Tolerance also develops to some of the side-effects of opioids making patients less likely to suffer from respira- Features Suggestive of Radiation-Induced Neuropathy. tory depression, itching and nausea than opioid naïve Progressive forelimb weakness (upper or lower arm patients. depending on which roots are involved), pain less common, initial involvement of upper plexus divisions, Acute Pain Management slow progression and long duration, and incidence increases with time. Management of pain in this population of patients is of increasing importance as the cancer survivor population Treatment. There are no standard treatments for radiation- grows and as greater numbers of patients are using con- induced BPN but opioids may be beneficial [151]. Other venient sustained release opioid preparations and trans- nonpharmacological treatments such as chemical sympa- dermal delivery systems.

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In general the issues of physical dependence, withdrawal In the preoperative and perioperative period regular and tolerance, only relate to patients who have been on opioids (usually oral) may be discontinued for several WHO Step 3 strong opioids such as morphine or oxyc- hours which amounts to the opioid “debt.” This should be odone for more than 1–2 weeks preoperatively. These replaced with systemic opioids during the operation. issues are not likely to be a problem in patients taking WHO Step 2 analgesics such as codeine or tramadol Parenteral Opioid Delivery. Transdermal drug delivery unless the patient is taking larger than normal doses. systems have the disadvantage of being relatively inflex- ible in their dosage delivery, with clinically relevant It is common to underestimate and undertreat pain in dosages still being absorbed for up to 12 hours. One opioid dependent patients, because most postoperative strategy is to leave the patch in place and to titrate to analgesic regimes are based on the opioid naïve patient. analgesic effect using immediate release opioids. Similarly, Opioid dependent patients should be identified preopera- it may be appropriate to leave implanted analgesic pumps tively and a perioperative analgesic plan should be throughout the perioperative period and use additional devised after discussions with the patients’ opioid pre- short acting opioid and nonopioids used to control break- scriber and with the pain team. The aim is to achieve through pain. effective analgesia without precipitation of withdrawal phenomena. Nonopioid Analgesia

Nonopioid analgesic drugs and local anesthetic proce- Opioid Management dures will have the effect of reducing opioid requirements—“opioid sparing effect” (e.g., nonsteroidal Management involves the regular provision of the pre- anti-inflammatory drugs [NSAIDs], paracetamol and cloni- existing opioid supplemented with additional short-acting dine). Local anesthetic blocks such as epidurals, brachial opioid, local anesthetic, nonsteroidal anti-inflammatory plexus block, paravertebral or ilioinguinal blocks will also drug and paracetamol. Patient-controlled analgesia with a have an “opioid sparing” effect. short lock-out and higher bolus dose may be useful. Neuraxial and regional analgesia is recommended where Effects of Surgery appropriate. Surgery itself will have a variable effect on opioid require- Patients will present for surgery having been on many ments and parenteral routes will have to be considered if different types of opioid for varying periods of time (e.g., the oral route is not available. It is difficult to predict the morphine, oxycodone, methadone, hydromorphone, precise postoperative analgesic requirements as the effect pethidine, etc.) which may be modified release (e.g., MST, of surgery may be to increase (if the surgery results in pain fentanyl patch) or immediate release preparations (e.g., due to local tissue trauma) or decrease opioid require- immediate release morphine). The route of delivery may be ments. Increases of 20% or more above the baseline oral, subcutaneous via a syringe pump or transdermal. opioid requirement have been reported, depending on the Dosages range from MST 10 mg twice a day to very large surgical procedure. However, surgery may alleviate pain doses such as MST 1 g per day or more. due to removal of direct tumor pressure effects on local structures (e.g., removal of a retroperitoneal sarcoma Standard postoperative opioid regimes are generally tumor pressing on the lumbosacral plexus). In this group developed for the opioid naïve patient. Patients on high of patients opioid requirements may reduce but they will dose opioids may have developed a physiological depen- still need baseline opioid administration. dence and if managed using standard postoperative anal- gesia regimes may not receive adequate analgesia and Complex Problems in Cancer Pain develop a “withdrawal syndrome.” This results in adrener- gic hyperactivity and common symptoms such as fatigue, Summary generalized malaise, abdominal cramps, perspiration, fever, piloerection, dehydration and restless sleep. Cancer pain is often very complex but the most intractable pain is often neuropathic in origin, arising from tumor Patients will require a baseline opioid dosage invasion of the meninges, spinal cord and dura, nerve postoperatively—referred to as the baseline opioid roots, plexuses and peripheral nerves. Accurate diagnosis requirement—calculated using their preoperative opioid of the causes of pain is necessary with the use of multi- dosage. This can either be given using the same opioid or modal therapies. Case studies illustrating some of these using an alternative opioid in an equi-analgesic dosage. A points are found in the British Pain Society document continuous parenteral infusion may be needed if the (http://www.britishpainsociety.org). patient is unable to take oral drugs. Provision will need to be made for “as required” dosing for breakthrough pain. Introduction Patient controlled analgesia machines have been suc- cessfully used in opioid dependent patients, their advan- Cancer pain can be complex and difficult to treat. Up to tage is that dosages and lock-out intervals can be 50% of patients may have pain at diagnosis and greater adjusted according to need. than 75% may experience pain with advanced cancer.

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Pain may occur in more than one site in over half of cases Pain from Cancer in People Who are Addicted and may have different etiologies. Such complexity can be to Opioids may be Undertreated for the challenging and require a truly multidisciplinary approach. Following Reasons As for nonmalignant pain, management of cancer pain can be challenging for the very young or old, for patients Lack of understanding of opioid addiction and methadone with medical problems such as heart disease, respiratory maintenance; lack of training on prescribing analgesia in disease, renal or liver compromise and those with mental this group of patients; attitude of health care professionals health issues. Often these factors may present in combi- about illicit drug users (fear of diversion); failure to recog- nation and generate demanding clinical problems. nize the potential for tolerance to other opioids in Methadone-maintained patients; acute pain may be Certain pain problems related to the nature of the pain or undertreated leading to misunderstandings, patient patient factors, may make the conventional WHO ladder anxiety, depression, dissatisfaction and complaints. approach to pharmacological therapy difficult to utilize and in some cases this approach may not be totally effective. Principles of Giving Analgesia in Other pharmacological or more invasive treatments may Opioid-Addicted Patients be required. Prevent withdrawal symptoms/complications; assess To exemplify such complex issues we will discuss case opioid load (in an intravenous [i.v.] drug user this is difficult; studies concerning problems of breakthrough pain; withdrawal symptoms can be prevented with low doses of cancer pain control in patients addicted to opioids; treat- opioids). ment of pain of mucositis; cancer pain in patients with dementia; alternatives to the conventional WHO ladder Diagnose the cause of the pain; nociceptive, inflammatory, approach; interventional procedures; ketamine. neuropathic, visceral, mixed. Use balanced analgesia wherever possible (NSAIDs, paracetamol, local anesthet- ics, tricyclic antidepressants, anticonvulsants). Use oral/ Breakthrough Pain transdermal/subcutaneous routes, not i.v. (consider epidural or intrathecal drug delivery systems, remember- Breakthrough pain has been referred to as a brief exacer- ing infection risk). bation of pain on a well controlled baseline. The terminol- ogy of “breakthrough pain” in undergoing subtle revisions Use long acting opioids and minimize analgesia for break- but is made up of many different types of pain. Break- through, as this may be rapidly escalated. Set a limit and through pain can be of any etiology. Certain authors feel review frequently. Use tablets (sevredol, oxynorm) for that “breakthrough pain” does not include exacerbations breakthrough pain, not oramorph. of pain in the titration phase, nor should end of dose exacerbation of pain be called “breakthrough” [153]. Make a “contract” with the patient before starting therapy, explaining the limitations, and setting a clearly defined Breakthrough pain can be divided into spontaneous: no upper limit of opioids before next review. Write clear obvious cause; incident pain: clear cause evident; nonvo- instructions for the whole team. litional: pain caused by involuntary act; volitional: pain caused by voluntary act; procedural: pain caused by Use a sole prescriber (usually GP). Prescriptions may have therapeutic procedure. to be issued daily, every 2–3 days, or weekly.

As for any cancer pain, treatment relies on detailed Use psychological therapies and treat anxiety and assessment and formulation of a multidisciplinary therapy depression. plan. Rapid acting opioids have been successfully used to treat breakthrough pain, but it remains a difficult therapeu- Maintenance Therapy tic problem. Newer preparations of rapid release opioids are being developed. Methadone substitution is the primary maintenance treat- ment in the UK, usually 60–120 mg daily. There may be tolerance to other opioids, and rapid escalation of doses Pain in Opioid Addiction and Substance Misuse can be dangerous, especially when combined with alcohol or other sedative drugs. In the United Kingdom, the prevalence of drug misuse is around 9 per 1,000 of the population aged 15–64 years, Naltrexone (opioid antagonist) is used in detoxification and around 3 per 1,000 inject drugs, in most cases programmes to help maintain abstinence. It is long acting opioids. Opioid abuse and dependence are associated (>48 hours) and will lead to opioid resistance and then with a wide range of problems, including overdose, HIV opioid sensitivity when it has been eliminated systemically. infection, hepatitis B or C, thrombosis, anemia, poor nutri- tion, dental disease, infections and abscesses, criminal Buprenorphine (partial agonist) is also used to prevent behavior, relationship breakdown, unemployment, impris- withdrawal symptoms in opioid dependent patients. Its onment, social exclusion and prostitution. action on the m receptors reduces the effects of any

888 Cancer Pain Treatments: Part 2 additional opioids. Average maintenance doses range A number of behavioral pain assessment tools for detect- between 12 and 24 mg daily. Patients with severe cancer ing the presence of pain in patients with dementia exist. pain may have to be changed from buprenorphine to Care providers are advised to select a tool that is appro- methadone. priate to the patient that can be used for initial and ongoing assessments. However, the assessment of Mucositis behavioral pain indicators should consider only one strat- egy to identify pain in patients with dementia and should Mucositis is the painful inflammation and ulceration of the be used in conjunction with other pain assessment strat- mucous membranes usually in the mouth but can affect egies and the evaluation of pain relieving interventions. other areas of the mucosa in the gastrointestinal tract [154,155]. It can be caused by radiation therapy or che- Atypical Pharmacological Treatments: Ketamine motherapy and very common after radiotherapy for cancer of the head and neck and after certain types of The N-methyl-D-aspartate (NMDA) receptor has been chemotherapy such as 5-fluorouracil. High dose chemo- implicated in mechanisms of neuropathic and inflamma- therapy and hematopoietic stem cell transplantation have tory chronic pain. It is one of the key components of especially high incidence of oral mucositis [155,156]. central sensitization that contributes to increased pain and abnormal pain perception. It is also thought to be involved Nonpharmacological treatment strategies include meticu- in many cancer pains. When the conventional WHO ladder lous oral hygiene, gel-based barrier protection, reduction approach fails, NMDA receptor antagonists could provide of known painful precipitants (e.g., alcohol), local anes- a novel and powerful site of analgesia. thetic mouth washes and other oral lubricants. Opioids provide the mainstay of pharmacological treatment but There is evidence for the efficacy of NMDA receptor newer anti-inflammatory therapies are being developed. antagonists in many chronic pains (including cancer pain), However, severe oral mucositis often causes difficulties in yet the situation is not so clear clinically. There are few swallowing precluding the use oral medication. NMDA receptor antagonists available. Dextromethorphan has been used for acute pain. Methadone also has some Pain in Dementia Sufferers NMDA antagonist activity and may help in some cases of opioid refractory pain. However, ketamine is the most Adults with dementia will probably express their pain in used NMDA receptor antagonist for cancer pain. ways that are quite different from their cognitively intact counterparts that can result in inadequate pain assess- Ketamine is an anesthetic, but in smaller doses appears to ment and consequently poor pain management. have analgesic properties. There are many case reports and case series demonstrating significant efficacy in The processing of sensory-discriminative aspects of pain refractory cancer pain either alone or concomitantly with in the brain are thought to occur in the lateral pain system, opioids. However, there is little higher quality evidence whereas motivational-affective aspects are processed by (such as RCTs) at present. The lack of data is reflected in the medial system. The recognition of these two systems the variability of suggested protocols in both dose and is important with patients with dementia. Pain thresholds route of administration. Side effects are potentially prob- (that are the sensory-discriminative aspects) do not differ lematic including tachycardia and cognitive disturbances between patients with Alzheimer’s disease and those such as hallucinations. Nevertheless, ketamine may older adults without dementia, although pain tolerance provide some empirical benefit in refractory cancer pain. (motivational-affective aspect) does. Older adults with Alzheimer’s disease perceive the presence of pain, but the Pain in Children and Adolescents with Cancer intensity and affective aspects are different to that expe- rienced by their cognitively intact counterparts. This might Pain in children and adolescents with cancer is a signifi- explain the atypical behavioral responses observed in this cant, debilitating, acute and chronic symptom, during or group. after treatment that affects the quality of life of young patients and their families. In recent years, advances in Observation of behavior for pain assessment in patients pain management have been made, however, still pain is who do not have the ability to communicate their pain can often undertreated and there is a need for improvement. be helpful but typical pain behaviors may be absent or difficult to interpret. Involvement of health care profession- The principles of pain management and palliative care in als, informal care providers and the family in the identifi- adult practice are relevant to pediatrics, nevertheless, the cation of pain is essential. adult model cannot be applied directly to children for the following reasons [158]: 1) the types of malignancy and The American Geriatric Society [157] list six categories of disease trajectory in children are different from those in pain behaviors and indicators for older people with adults; 2) special considerations are required when select- dementia: facial expressions; verbalizations and vocaliza- ing analgesics, doses and modalities during childhood. tions; body movements; changes in interpersonal interac- Factors that influence prescribing are quite distinctive from tions; changes in activity patterns or routines; mental adults and include metabolism, renal clearance, changing status changes. size and surface area, and the ability to manage medica-

889 Raphael et al. tion, among others; 3) a child’s family and social context is 7 Bates MS, Edwards WT, Anderson KO. Ethnocultural different to that of an adult: relationships with parents and influences on variation in chronic pain perception. siblings, school and friends, extended family network are Pain 1993;52:101–12. of paramount importance when treating young patients; 4) children’s developmental stage and continuous psycho- 8 Breitbart W, Payne D, Passik SD. Psychological logical, spiritual and cognitive development need to be factors in pain experience. In: Doyle D, Hanks G, taken into account when treating their pain (e.g., a child’s Cherny N, Calman K, eds. Oxford Textbook of Pallia- conceptualization of what causes and eases pain, under- tive Medicine, 3rd edition. Oxford: Oxford Press; standing of time, ability to implement behavioral and cog- 2004:425–6. nitive strategies for coping with pain) and 5) the legal and moral positions regarding the decision-making ability of 9 Strong J, Sturgess J, Unruh AM, Vicenzino B. Pain both those with parental responsibility and the child/ assessment and measurement. In: Strong J, Unruh young person themselves is very different to that of an A, Wright A, Baxter G, eds. Pain. A Textbook for adult. Therapists. Edinburgh: Churchill Livingstone; 2002:123–47. Effective pain management in children and young people with cancer requires that pediatric health care providers 10 Simmonds M. Physical function and physical perfor- take into account the multitude of physiological and psy- mance in patients with pain: What are the measures chological changes that occur from infancy through ado- and what do they mean? In: Max M, ed. Pain 1999 lescence, including changes in relationships with parents An Updated Review. Refresher Course Syllabus. [159]. The multidisciplinary approach to providing pain Seattle, WA: IASP press; 1999:127–36. management for children and adolescents includes inte- grating pharmacological and psychosocial care in the 11 Serlin C, Mendoza TR, Nakamura Y, Edwards KR, context of each patient’s physical, cognitive, emotional Cleeland CS. When is cancer pain mild, moderate or and spiritual level of development [160]. severe? Grading pain severity by its interference with function. Pain 1995;61:277–84. Every child/young person with pain management and pal- liative care needs should have access to universal pedi- 12 Cleeland CS, Ryan KM. Pain assessment: Global use atric services, core palliative care services (hospice, of the Brief Pain Inventory. Ann Acad Med Singap community palliative care nurses) and specialist palliative 1994;23(2):129–38. care support when required [161]. 13 Baptiste S, Law M, Pollock N, et al. The Canadian occupational performance measure. WFOT Bull References 1993;28:47–51. 1 Gysels M, Higgenson IL. Improving Supportive and Palliative Care for Adults with Cancer. NICE Guid- 14 Melzack R. The McGill Pain Questionnaire: Major ance on Cancer Services. 2004. Available at: http:// properties and scoring methods. Pain 1975;1:277– nice.org.uk (accessed March 25, 2010). 99.

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