Haemophilia (2014), 20, e113–e120

DOI: 10.1111/hae.12349

REVIEW ARTICLE

Comprehensive management of chronic pain in haemophilia G . Y O U N G , * R . T A C H D J I A N , † K . B A U M A N N ‡ and G . P A N O P O U L O S ¶ *Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California; †Division of Clinical Immunology and Allergy, David Geffen School of Medicine at UCLA, Los Angeles, CA; ‡Center for Bleeding and Clotting Disorders, University of Minnesota, Fairview Medical Center; and ¶Fairview Pain Management Center, University of Minnesota, Minneapolis, MN, USA

Summary. Chronic pain, most often due to haemophilic arthropathy, is a pervasive problem in persons with haemophilia (PWH) that adversely impacts function and quality of life. PWH with inhibitors and older PWH may be especially vulnerable to progressive arthropathy and resulting chronic pain. The development of chronic pain from acute pain involves a complex interplay of biological and psychosocial factors that may all contribute to the perpetuation of chronic pain and the outcome of therapy. In the absence of evidence-based guidelines, an individualized, multimodal approach to chronic pain management is proposed, as it is in individuals without haemophilia who have chronic pain. Pharmacological treatment is central to the management of chronic pain and must be modified based on pain intensity, ongoing response to therapy and the risk for adverse events. Non-pharmacological interventions,

including physiotherapy, complementary treatments and surgical (e.g. orthopaedic) or other invasive procedures, may be integral to chronic pain management in this population. Ongoing psychosocial assessment is critical to identify those factors that may be contributing to the perpetuation of chronic pain or acting as barriers to effective management. Additional study is needed to identify optimal pharmacological treatments for chronic pain in PWH based on the unique pathophysiology of haemophilic arthropathy and on risk profile. Systematic determination of the particular psychosocial factors impacting the experience and management of chronic pain in PWH would likewise add value to the treatment of this pervasive problem.

Introduction

centrate in some parts of the world, cost, and the need for reliable venous access, not all persons with haemophilia (PWH) are afforded the benefits of prophylaxis [1–3]. Furthermore, the efficacy of secondary prophylaxis may be limited in PWH who have already developed arthropathic changes [2]. Options for prophylaxis are likewise limited in PWH with inhibitors, who are especially susceptible to the development of chronic arthropathy. Finally, older PWH may not have had the option of primary prophylaxis during childhood [4], before it became standard of care. Consequently, a subset of PWH remains susceptible to the development of chronic arthropathy, a leading cause of persistent or chronic pain in this population. Despite being a pervasive problem, chronic pain is suboptimally treated in PWH. Information regarding the nature and optimal management of chronic pain in this population is exceedingly limited. The purpose of this review is to explore the development and perpetuation of chronic pain in PWH, particularly with regard to psychosocial and developmental inputs,

Congenital haemophilia A and B are characterized by deficiencies of factor VIII (FVIII) and factor IX, respectively, resulting in a poorly functioning coagulation system and increased propensity for bleeding. More severe disease tends to present in early childhood, predominately with recurrent musculoskeletal bleeding such as haemarthroses, the hallmark of haemophilia [1]. In the past few decades, clotting factor prophylaxis has been increasingly adopted as a means to reduce the incidence of haemarthroses and, ultimately, the development of chronic arthropathy [2]. However, because of limited access to factor conCorrespondence: Guy Young, MD, Director, Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Mail Stop #54, Los Angeles, CA 90027, USA. Tel.: (323) 361 5507; fax: (323) 361 7128; e-mail: [email protected] Accepted after revision 21 November 2013 © 2013 John Wiley & Sons Ltd

Keywords: analgesia, arthropathy, chronic pain, haemarthrosis, haemophilia, synovitis

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and to explore the therapeutic options for chronic pain in PWH, with emphasis on a multimodal approach.

Scope of chronic pain in persons with haemophilia Chronic pain is variably defined based on a fixed duration of pain (typically 3 months or more) or on the persistence of pain beyond the expected time frame for healing after tissue injury. Therefore, defining ‘chronic pain’ in any given population is important, as not every definition of the term will necessarily apply to every population. The European Haemophilia Therapy Standardisation Board (EHTSB) proposed a definition for chronic pain in PWH that encompasses continuous or intermittent pain, which occurs more than once weekly for a period of 3 months or more [5]. Additional qualifiers in their definition included the need for pharmacological or non-pharmacological treatment and an inability to readily remove the cause of the pain [5]. Several studies have suggested that chronic pain is a pervasive problem in PWH. In one study, adults with severe haemophilia (N = 71) reported ‘major’ pain in an average of four joints [6]. Nearly one third claimed that pain treatment was ineffective, despite regular (3– 4 per year, on average) haemophilia treatment centre (HTC) visits [6]. In the multinational Hemophilia Experiences, Results and Opportunities (HERO) Study, 50% of surveyed adults with all severities of haemophilia reported ‘constant pain,’ although the source of pain was not specified [7]. Among more than 700 adults with haemophilia in the United States who participated in the prospective National Pain Study, a mean daily persistent pain level of 4.22/10 was reported, and 39% of PWH reported that their pain was insufficiently treated [8]. In a survey of 22 European HTCs providing care to more than 6000 PWH, 35% of adults and 8% of children were identified specifically as having ‘chronic pain’ [5]. Above and beyond the joint fibrosis and deformity that contribute to restricted range of motion (ROM) in more severe cases, pain itself may drive some of the functional impairment reported by PWH with haemophilic arthropathy [9]. Persistent pain has been identified as a significant determinant of health-related QOL (HRQOL) in both children and adults with haemophilia [7,10]. In the HERO Study, 89% of adults with haemophilia indicated that pain interfered with their daily lives; 54% of adults with haemophilia in this study reported that pain interfered with their daily lives moderately to extremely so [7]. Specifically, arthropathic pain has been associated with adverse impacts on employment status and mood in PWH [6]. Severe joint pain in particular is associated with significantly higher health care costs and consumption of resources,

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including pain medications and factor concentrates [11], the latter of which may be used inadvertently to treat pain that is thought to be due to a bleed but is instead due to arthropathy. Other unquantified societal costs include those related to lost productivity in the workplace, whether due to disability or, in those who are employed, absenteeism or impaired productivity. The presence of inhibitors increases the probability that severe arthropathy will develop, because bleeding episodes are more difficult to treat and prevent and may be prolonged [12]. Inhibitors have been associated with greater joint ROM limitations [13] and impaired HRQOL, the latter of which has been shown to correlate with orthopaedic status (as measured by a modified version of the World Federation of Hemophilia Orthopedic Joint Score) [14]. Among 52 persons with severe haemophilia and inhibitors from Italy, 81% were disabled, 71% reported some or moderate pain, and 4% reported ‘extreme’ pain [15]. Children with inhibitors have been shown to experience significantly more frequent joint bleeding and have significantly more target joints compared with children without inhibitors [16]. Furthermore, whereas children without inhibitors who are on prophylaxis rarely experience joint pain of a chronic nature, children with inhibitors are susceptible to this complication [5]. Similar to clotting factor prophylaxis in PWH without inhibitors, prophylactic treatment with bypassing agents may attenuate the increased risk of haemarthroses and arthropathy in PWH with inhibitors but awaits additional, more rigorous systematic evaluation [17]. Like those with inhibitors, older PWH may be more susceptible to chronic arthropathic pain and disability given that arthropathy is likely to worsen with age [18].

Development and perpetuation of chronic/ persistent pain in persons with haemophilia It is useful to consider persistent pain in PWH in the same way that non-haemophilia-related chronic pain is normally regarded: as a complex interaction among biological, psychological, and social factors [19]. There are physiological and behavioural adaptations to chronic pain, similar to any recurrent or ongoing stressor. Recurrent or chronic pain induces a physiological stress response comprising various neuroendocrinological alterations, such as activation of the sympathetic nervous system and changes in brain structure and function, particularly within the limbic system [20]. These physiological changes are initially beneficial but over time may become maladaptive, if there is failure to habituate to the stressor or to ‘shut down’ the stress response [20]. Persistent pain may also induce various modifications in behaviour intended to minimize or thwart actual or anticipated pain. These behavioural

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responses may also become counterproductive; for example, ongoing avoidance of activity may worsen any disability associated with chronic pain [21]. How one thinks about chronic pain may also have a profound influence on the magnitude of pain and disability and on the success of therapeutic interventions [21]. Common cognitive distortions related to chronic pain include all-or-nothing thinking (e.g. ‘I am always in pain’ or ‘This pain will never go away’), overgeneralization (e.g. if one medical intervention does not control pain, none of them will), and catastrophizing (i.e. assuming the worst without considering more realistic possibilities) [22]. Catastrophizing in particular has been identified as a psychological risk factor (or ‘yellow flag’) for poor outcomes in individuals with low back pain [21]. Certain beliefs regarding pain (e.g. ‘hurt is harm,’ ‘rest is best’) may likewise intensify or perpetuate chronic pain and disability [21]. Psychosocial factors may also contribute to the intensification or perpetuation of chronic pain. Affective disorders such as depression or anxiety and sleep disturbance can reciprocally exacerbate chronic pain and disability. Family and other interpersonal relationships may be adversely affected by chronic pain. Conversely, family dynamics may influence outcomes in chronic pain. For example, family emphasis on autonomy and personal achievement has been associated with positive outcomes in adults with chronic illness, whereas critical, overprotective, or controlling family responses have been associated with negative outcomes [23]. There may be additional developmental considerations in the development and perception of chronic pain among PWH, given that haemophilia is a condition that spans the entire life cycle from childhood to adulthood. Painful episodes are likely to begin in childhood, especially in the setting of moderate or severe disease. In general, children must rely upon others to recognize and alleviate their pain. This lack of autonomy or control over pain may lead to adverse emotions and thoughts about pain such as helplessness or a tendency to focus on or feel threatened by pain, any of which may heighten pain perception or intensity and disability [19]. Poorly managed episodes of acute pain in children may lead to fear of medical treatment, in addition to contributing to some of the aforementioned maladaptive thoughts and their consequences. Parental attitudes and responses towards pain (e.g. catastrophizing) may also augment pain perception and intensity in the affected child [24]. Avoidance of activity due to heightened fear of pain or injury exacerbates debilitation and pain (or lowered pain tolerance) and, potentially, social isolation [21] at a critical time in development. It is presumed that these thoughts and behaviours ultimately inform how chronic pain is perceived, experienced and dealt with, even into adulthood. © 2013 John Wiley & Sons Ltd

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Additional study is needed to determine the unique developmental and psychosocial factors impacting the development, perpetuation and management of chronic pain in PWH across the life cycle. Determination of these factors and how they uniquely impact the experience of chronic pain in this population may have important therapeutic implications. For example, it may be counterproductive to discourage fear avoidance or encourage pain acceptance altogether in this population because there are measures that PWH can take to prevent or minimize the underlying pathology of their pain (namely, bleeding and subsequent joint damage), in contrast to other chronic pain conditions. Pending additional investigation of these issues, the health care team should make every effort to identify and address emotional, psychological, social and cultural barriers to effective chronic pain management in PWH.

Management options for chronic pain in persons with haemophilia Clinical studies assessing pharmacological and nonpharmacological therapies for pain in PWH are limited; therefore, there are no evidence-based guidelines for the management of chronic pain in this population. The EHTSB has published consensus recommendations for the assessment and treatment of chronic pain in PWH that were based on a review of the literature, expert opinion and consultation within the EHTSB network [5]. Ultimately, there is a need for a more standardized approach to the assessment and management of chronic pain in PWH by HTCs and other providers, including criteria for involving a pain specialist. In the meantime, an interdisciplinary, multimodal approach similar to that recommended for management of chronic pain in general is advocated. Optimal chronic pain management will likely consist of a combination of pharmacological therapies and non-pharmacological interventions (Fig. 1), such as physiotherapy, complementary therapies, surgery or other invasive procedures, or psychosocial interventions.

Pharmacological therapies Because the systematic evaluation of pharmacological therapies for chronic pain in PWH is limited, the recommended approach to analgesia in this setting has been extrapolated from that for other forms of non-cancerrelated chronic pain, with adaptations to limit any increased risk for bleeding or other complications specific to this population (Fig. 1). The foundation of this approach is the World Health Organization’s Pain Relief Ladder [25], which was developed to guide the management of cancer-related chronic pain but has been adopted for non-cancer-related chronic pain as well. Considerations for common analgesic therapies in PWH are outlined in Table 1 [5,6,26–36] and are Haemophilia (2014), 20, e113--e120

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Pain persisting or increasing

3 Pain persisting or increasing

2 COX-2 selective or nonselective 1 NSAIDs† or acetaminophen + Acetaminophen* weak opioid (adults and children) (adults)

Tramadol or strong opioid ± non-opioid (adults) Refer to pain specialist (children)

Acetaminophen + weak opioid (children)

• Physiotherapy • Complementary • Psychosocial

Fig. 1. Schematic of management strategies for chronic pain in adults and children with haemophilia. Analgesic therapy should be escalated as needed based on persistence of or increase in pain [5], with ongoing application of the non-pharmacological interventions shown. COX-2, cyclooxygenase-2; NSAID, non-steroidal anti-inflammatory drug. *Liver function should be monitored and maximum doses should be reduced if used in the setting of mild or moderate liver dysfunction [5]. †Use NSAIDs with caution in individuals with cardiovascular disease or risk factors [use least COX-2 selective agents (e.g. ibuprofen, naproxen) and avoid long-term use] [5]. Consider coadministration of a proton pump inhibitor during NSAID therapy [5].

extensively reviewed elsewhere [5,37]. Typical firstline therapy for chronic pain consists of a non-opioid analgesic medication such as acetaminophen or nonsteroidal anti-inflammatory drug (NSAID), which are the analgesic agents used most often for treatment of acute or chronic pain in PWH [5,8]. For the most part, NSAIDs have not been associated with bleeding or platelet dysfunction in PWH [29,32], with the exception of aspirin, which has been shown to adversely affect platelet function in individuals with haemophilia [6]. Cyclooxygenase-2 (COX-2)–selective inhibitors [30,31,34] may be used in lieu of non-selective NSAIDs when bleeding is a particular concern; however, NSAIDs that are strictly or more COX-2 selective should be used with caution in individuals with cardiovascular risk factors, given the association of such NSAIDs, in particular, with cardiovascular thrombo-occlusive events [26]. When pain persists or increases despite treatment with a non-opioid agent and appropriate adjunctive therapies, an opioid may be indicated [25]. The specific agent should be selected based on pain intensity (mild-to-moderate vs. moderate-to-severe), generally escalating from ‘weaker’ to ‘stronger’ opioids as needed (Fig. 1). Other pharmacological agents that may be used for the treatment of chronic pain include anticonvulsants [i.e. alpha-2-delta calcium–channel antagonists (pregabalin or gabapentin), sodium-channel antagonists, Haemophilia (2014), 20, e113--e120

or membrane-stabilizing anticonvulsants], specifically, for neuropathic pain, or antidepressants [5]. Systemic or intra-articular steroids have also been proposed for the treatment of chronic arthropathy-related pain. Intra-articular methylprednisolone [38] and dexamethasone [39] both have been shown to subjectively improve symptoms attributable to chronic haemophilic synovitis in the short to medium term in small, uncontrolled studies. Objective measurements of ROM, pain, joint thickening and functioning in activities of daily living (ADLs) were also improved in the majority of PWH for an average of 1.5 years after intra-articular dexamethasone in the latter study [39]. Factor concentrate is often used to treat chronic pain, presumably because pain from chronic arthropathy is erroneously attributed to acute haemarthrosis [4,8]. More than half (58%) of PWH in the National Pain Study reported using factor replacement to treat persistent pain [8]. In another study, 43% of individuals with severe haemophilia A and ‘constant’ pain reported that their pain was sufficiently managed with FVIII concentrate alone [6]. Although the authors of the latter study found the apparent analgesic effect of FVIII to be noteworthy in the setting of chronic arthropathy, possibly warranting additional study [6], factor replacement should be deferred in favour of less costly, more effective analgesic therapies for the time being. To this end, HTCs may be able to assist patients in differentiating haemarthrosis-related pain from that related to arthropathy [4]. It should be noted that studies to date have included limited numbers of PWH with inhibitors; therefore, current strategies and best options for chronic pain management in this subpopulation are not known. In the absence of evidence, it may be prudent to avoid medications that may be associated with an increased risk of bleeding (e.g. non-selective NSAIDs) in PWH with inhibitors. To avoid inadvertent overdosing, all PWH who are receiving acetaminophen-containing products or NSAIDs for treatment of chronic pain should be advised to monitor their intake of over-thecounter products containing these agents.

Non-pharmacological therapies and interventions Physiotherapy. Physiotherapy has been associated with benefits in PWH with joint disease, specifically the reduction in pain. In an analysis of adults with severe haemophilia and an average of 4.4 painful joints who underwent an intensive 4-week clinical rehabilitation programme, 13 of 15 PWH rated their pain, walking distance and ability to perform ADLs as improved or equal 5 years later [40]. Mean ROM in the knee, elbow and ankle remained stable after 5 years [40]. Among 93 adults with haemophilia of all severities participating in a survey study spanning approximately 3 years, mean pain intensity visual analog scale © 2013 John Wiley & Sons Ltd

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Table 1. Considerations for common analgesic therapies in persons with haemophilia. Analgesic agent Acetaminophen

NSAIDs COX-2 selective inhibitors

Preferred first-line agent for adults and children with haemophilia and chronic pain without chronic liver disease [5] Consider monitoring hepatic transaminases with prolonged daily use [maximum daily doses (4 g/day) associated with alanine aminotransferase elevation in healthy adults [35]] May be considered a first-line therapy in younger adults [5] May consider in lieu of nonselective NSAIDs given the risk for (especially gastrointestinal) bleeding Rofecoxib, celecoxib, and etoricoxib shown to be efficacious and safe for treatment of chronic arthropathy- or synovitis-related pain in PWH [30,31,34] Associated with adverse cardiovascular thrombotic events including myocardial infarction and stroke •

Use with caution in setting of cardiovascular disease or risk factors



Monitor recipients for hypertension or other evidence of cardiovascular disease [26]

Unclear whether risk would be mitigated in PWH, especially those with severe haemophilia, who may be less susceptible to thrombo-occlusive events Celecoxib is only COX-2 inhibitor on the market in the US



Non-selective

Opioids

Ibuprofen shown to be effective and safe in two small, placebo-controlled studies in PWH, without any clinical or laboratory evidence of impaired platelet function [29,32] Transdermal NSAIDs (e.g. diclofenac) may offer a safer alternative to oral formulations (lower incidence of systemic AEs) [36], though their use has not been reported in PWH Also carry a risk of adverse cardiovascular events, particularly those that are more COX-2 than COX-1 selective (e.g. diclofenac) [26]; therefore, use with caution in setting of cardiovascular disease or risk factors (see recommendations for COX-2 inhibitors above) Aspirin should not be used for analgesia in PWH; has been shown to adversely affect platelet function (particularly in severe haemophilia) [6] ‘Weaker’ opioids (e.g. codeine or hydrocodone [28]) typically used initially, often in formulations containing acetaminophen Tramadol, a weak Mu opioid receptor agonist that also promotes serotonin release and prevents norepinephrine reuptake, may be used initially in lieu of weaker opioids or even as a first-line agent for treatment of chronic pain in PWH [5] ‘Stronger’ opioids such as oxycodone, fentanyl, morphine, or hydromorphone [28] may be used when a trial of a weaker opioid fails to provide pain relief or in the setting of severe pain Optimally used for short-term pain management; long-term (≥6 months) effectiveness is variable [33] Long-acting formulations may be appropriate to achieve sustained analgesia, although with a delayed onset of action [27]; in contrast, short-acting formulations have a quicker onset of action but a shorter duration [27] •

Both types of formulations are equally efficacious [27]

While the use of long-acting opioids allows for less frequent dosing and may thus be helpful in the setting of unremitting pain, short-acting opioids may be more appropriate when a rapid onset of analgesia is preferred [27] Common adverse effects include constipation, nausea, vomiting, pruritus, and somnolence Tolerance and physical dependence must be differentiated from addiction





Tolerance: the need for higher doses with longer term opioid use



Physical dependence: development of a withdrawal syndrome after rapid dose reduction or cessation following long-term use



Tolerance and physical dependence are expected physiological phenomena; in contrast, addiction involves additional compulsive psychological and behavioural components, such as craving, compulsive and continued use despite negative consequences, and impaired control over drug use [33]



Individuals with insufficiently treated pain may exhibit behaviours normally associated with addiction, a phenomenon known as ‘pseudoaddiction.’ Satisfactory treatment of pain will lead to the cessation of addictive-type behaviours in pseudoaddiction

AE, adverse event; COX, cyclooxygenase; NSAID, non-steroidal anti-inflammatory drug; PWH, persons with haemophilia; US, United States.

(VAS) scores decreased by 26% (from 4.2 to 3.1) in those who attended physiotherapy over the study period and by 4.6% (from 4.3 to 4.1) in those who underwent a course of inpatient rehabilitation [41]. In contrast, VAS scores rose by 8% (from 3.6 to 3.8) among those who did not attend physiotherapy [41]. Current evidence suggests that physiotherapy may be underutilized for the management of persistent pain in PWH: only 30% of PWH in the National Pain Study [8] and 16% of PWH in a preceding pilot study [42] utilized physiotherapy for persistent pain. The reasons for this underutilization were not clear considering that all participants were affiliated with HTCs, which normally incorporate physiotherapy as a key component of their model for care [42]. In addition, © 2013 John Wiley & Sons Ltd

although the first three components of rest, ice, compression and elevation (RICE) were used more often by participants in the National Pain Study than any analgesic medication to treat persistent pain, less than 60% of respondents used ice, compression and elevation for this purpose [8]. The authors of the study concluded that these findings highlighted an area for added reinforcement by the physiotherapist and other members of the HTC team, recommending ongoing emphasis of RICE for chronic pain management to PWH on annual HTC visits [42]. Other physiotherapeutic interventions that may be helpful in managing chronic pain include targeted stretching and strengthening techniques, splinting, orthotics, transcutaneous electrical neurostimulation, therapeutic ultrasound and Haemophilia (2014), 20, e113--e120

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hydrotherapy [12,37]. Identification and modification of specific activities by a skilled physiotherapist may be required for individual PWH based on their target joints. Perhaps more than any other traditional aspect of chronic pain management in PWH, psychosocial factors may have a profound impact on the adherence to and success of physiotherapy. Therefore, attention to some of these factors may enhance physiotherapeutic outcomes [21]. In addition to physiotherapy, regular exercise of some form should be encouraged, as this may improve general sense of well-being in the individual with chronic pain in addition to providing physical benefits. In a retrospective study, adults with haemophilia who engaged in 30 min of exercise at least three times per week had a significantly greater mean increase from baseline in ROM across multiple joints (+3°) when compared with a cohort that did not engage in regular exercise (0°) [43]. Weight control is another important goal of regular exercise, particularly given that obesity may exacerbate joint damage in PWH, especially in weight-bearing joints [44]. Complementary therapies. Less than one third of PWH in the National Pain Study reported using various complementary therapies to manage persistent pain [8]. While many of these therapies have been systematically evaluated in the setting of non-haemophilia-related chronic pain and have become increasingly legitimized for this purpose, most complementary therapies have been minimally, if at all, evaluated in PWH. Acupuncture has been evaluated for chronic pain treatment in PWH in two small studies, only one of which was controlled. In a small study of nine adults with haemophilia of all severities, seven reported improvement in pain VAS ratings after a total of 14 acupuncture sessions [45]. Four PWH in this study reported at least a 50% improvement in VAS ratings, including one individual with severe haemophilia B whose rating dropped from 10 to 5 [45]. The frequency of analgesic use was reduced in three of these PWH [45]. Improvements in seven of nine mean QOL domains on the Short Form36 (SF-36â; QualityMetric, Lincoln, RI, USA) were also noted following treatment [45]. In another study of 12 adults with severe haemophilia and painful arthropathy of both lower extremities who received 15 cycles of acupuncture on only one side, 10 reported a reduction in their pain on the treated side; average VAS decreased from 6.8 to 5.0, whereas it remained essentially unchanged on the untreated side (4.1–4.0) [46]. No bleeding complications were attributed to acupuncture therapy in either study, including in PWH who were not pretreated with factor. Other complementary therapies that employ activities or practices that shift the individual’s attention away from their pain have been utilized for chronic pain management. Music therapy, which involves the Haemophilia (2014), 20, e113--e120

therapeutic use of music or musical activities, has been shown to be an effective treatment for various chronic pain conditions [47–49] but has not been systematically studied specifically in PWH. Self-hypnosis has been associated with reduced factor usage, an improved sense of well-being and QOL and reduced stress in children and adults with haemophilia [50]. Other combined self-regulation techniques (progressive muscle relaxation, meditative breathing and guided imagery) have been anecdotally shown to reduce pain intensity and analgesic dependence in a child with severe haemophilia and an inhibitor [51] and in three adults with severe haemophilia [52,53], all of whom had marked arthropathy. In essence, pain-management methods utilizing complementary and alternative medicine aim to create guided imagery to reorganize and perhaps ‘rewire’ upward- and downward-bound neuronal signals. Hallmarks of successful therapy include strategies that help the individual differentiate between arthritic pain and pain caused by an active bleed (e.g. haemarthrosis). Invasive interventions. Similar to steroids, intra-articular injection of hyaluronic acid, also known as viscosupplementation, has been proposed as a treatment for haemophilic arthropathy. A recent prospective study showed that PWH with haemophilic arthropathy of the knee, elbow, or ankle who received at least two cycles of viscosupplementation over a mean period of 6.3 years experienced significant improvements in WFH scores, VAS ratings, and SF-36 scores at 6 months after initiating therapy; significant ROM improvements were also noted in some joints 6– 12 months after initiating therapy [54]. There were no adverse effects reported. Other studies have likewise reported improvements in pain and function in PWH with arthropathy after viscosupplementation for a period of up to 10 years [55–57]; however, the improvements were generally subjective and not statistically significant in all cases. In addition, improvements generally peaked in the first 6 months to year after initiating treatment. Pending larger, well-designed clinical trials, questions remain as to whether the short-term benefits derived from viscosupplementation justify the costs (especially of protective factor replacement) and potential risk of this procedure in PWH [58]. Surgical interventions may be undertaken when the aforementioned pharmacological and non-pharmacological measures fail to provide sufficient relief from pain or improvements in function. Synovectomy may be performed in the interim as a means to reduce the probability of haemarthroses. Total joint replacement has been shown to provide pain relief in the setting of advanced haemophilic arthropathy [59]. Individuals undergoing this procedure, however, must be prepared for a challenging postoperative course that includes intensive rehabilitation. In addition, despite the intent © 2013 John Wiley & Sons Ltd

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to alleviate pain with this procedure, persons who undergo arthroplasty can develop chronic pain after the procedure [60]. Close communication among the PWH, HTC team, and orthopaedic surgeon is critical for ensuring a cohesive plan (and expectations) for perioperative pain management and preprocedural and postprocedural rehabilitation. Psychosocial assessment and intervention. Psychosocial assessment should be ongoing in PWH with chronic pain, given the potential impact of various emotional, psychological, and social factors on the perpetuation and successful management of chronic pain. Psychosocial distress may likewise result from the ongoing experience and burden of chronic pain. Psychological or psychiatric evaluation may be warranted when the presence of an affective disorder is suspected. Cognitive behavioural therapy may be used to challenge cognitive distortions and beliefs related to chronic pain, ideally allowing the individual to put pain in perspective and adopt positive (i.e. adaptive) coping strategies [19,37]. Providers should pay attention to the impact of chronic pain on activities such as work, school, or sleep and intervene as indicated. In particular, improved pain control may be warranted in individuals with sleep disturbance [27], as poor sleep may be an indicator of suboptimal pain control [61] and may contribute to the chronicity of pain [19]. Finally, patient or caretaker education is critical, to facilitate proactive disclosure of chronic pain and ensure appropriate responses to and management of pain. Educational efforts can help in redirecting some of the maladaptive emotional, behavioural, and cognitive responses that individuals may have about chronic pain towards efforts to better understand the nature of their pain, plan self-care strategies and to wisely

References 1 Acharya SS. Exploration of the pathogenesis of haemophilic joint arthropathy: understanding implications for optimal clinical management. Br J Haematol 2012; 156: 13–23. 2 Iorio A, Marchesini E, Marcucci M et al. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database Syst Rev 2011; 9: CD003420. 3 Shapiro AD. A global view on prophylaxis: possibilities and consequences. Haemophilia 2003; 9: 10–17. 4 d’Young I, Young L, Brasser M et al. Chronic arthropathy management in haemophilia: assessing the impact of a new model of care. N Z Med J 2012; 125: 161–3. 5 Holstein K, Klamroth R, Richards M et al. Pain management in patients with haemophilia: a European survey. Haemophilia 2012; 18: 743–52.

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utilize support systems and resources [21]. PWH or their caregivers should be considered part of the health care team and thus integral to all decision-making in the management of this complex problem.

Conclusions Evidence suggests that chronic pain is a pervasive yet suboptimally treated problem in PWH. Additional study is needed to identify the best pharmacological treatments for chronic pain in PWH, including those with inhibitors, taking into account the unique pathophysiology of haemophilic arthropathy and the risk profile in this population. Additional study is also warranted to elucidate the particular psychosocial factors that contribute to perpetuation of chronic pain or that serve as obstacles to effective chronic pain management in PWH. In the meantime, an individualized, multimodal approach incorporating both pharmacological and non-pharmacological therapies is advocated for optimal management.

Acknowledgements Dr Young, Dr Tachdjian, Ms. Baumann, and Dr Panopoulos all contributed to the conceptualization, content, and composition of this article. Writing assistance was provided by Lara Primak, MD, of ETHOS Health Communications in Newtown, Pennsylvania, with financial support from Novo Nordisk Inc, in compliance with international Good Publication Practice guidelines. None of the authors received remuneration of any kind for the development of this manuscript.

Disclosures Kimberly Baumann has previously been a paid speaker for Novo Nordisk Inc, unrelated to this manuscript. Guy Young, Raffi Tachdjian and Georgia Panopoulos stated that they had no interests that might be perceived as posing a conflict or bias.

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Comprehensive management of chronic pain in haemophilia.

Chronic pain, most often due to haemophilic arthropathy, is a pervasive problem in persons with haemophilia (PWH) that adversely impacts function and ...
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