Haemophilia (2014), 1–11

DOI: 10.1111/hae.12526

ORIGINAL ARTICLE

Managing chronic pain in adults with haemophilia: current status and call to action T . J . H U M P H R I E S * and C . M . K E S S L E R † *Bayer HealthCare, Whippany, NJ, USA; and †Georgetown University Medical Center, Washington, DC, USA

Summary. Haemophilic arthroses are associated with acute pain during bleeding episodes and with chronic pain caused by arthritic complications of repeated bleeding into joints. Unlike other conditions (e.g. osteoarthritis, rheumatoid arthritis, sickle cell disease), there are limited data on pain management in haemophilia. Management of arthritic individuals and those with sickle cell disease relies heavily on administration of acetaminophen, non-steroidal antiinflammatory drugs (NSAIDs) and opioid analgesics. In haemophilia, acetaminophen often has limited efficacy at therapeutic doses, offering a narrow dosing range in those with liver disease due to chronic hepatitis C. NSAIDs can effectively manage pain in patients with haemophilia, but these agents are potentially associated with a significant risk of precipitating or exacerbating bleeding complications in an already coagulopathic population. Opioids have proven effective in osteoarthritis and sickle cell disease, but outcomes data in those with haemophilia

are virtually non-existent. Patients with haemophilia are at least as vulnerable as other chronic pain populations to opioid-related adverse events and to developing abusive behaviours and addiction. Despite pain management strategies for patients with haemophilia being far from optimal, the predominant precept of haemophilia management still applies. As such, it is critically important to aggressively reverse or prevent acute symptomatic bleeding in a timely and effective manner to at least minimize pain and progressive joint damage. This review should serve as a call to action to prioritize pain management in haemophilia care and spur interest in the development, improvement and standardization of tools to assess and manage acute and chronic pain in haemophilia.

Introduction

chronic pain caused by arthritic complications of repeated bleeding into joints [2]. Published data indicate that 15% to >50% of adults with severe haemophilia experience chronic pain [3–7]. In a survey of 675 patients with haemophilia, 38% with haemophilia A, 42% with haemophilia B and 32% with haemophilia with inhibitors reported chronic pain related to haemophilia [7]. An additional 5–8% of patients reported chronic pain unrelated to haemophilia. The chronic pain and subsequent arthropathy contribute substantially to loss of joint function and impaired health-related quality of life (HRQoL) [8–10]. The prevalence of pain appears to be even higher in the cohort of patients who were maintained with on-demand treatment rather than secondary prophylaxis replacement regimens and in those with alloantibody inhibitors, of whom up to 71% of subjects in one study reported mild-to-moderate pain and 4% reported extreme pain [11]. Yet, in contrast to more common conditions characterized by chronic joint point [e.g. osteoarthritis (OA), rheumatoid arthritis

Severe haemophilia A (factor VIII deficiency) and B (factor IX deficiency) are characterized by episodes of uncontrolled bleeding that may be either spontaneous or trauma induced. The consequences of intra-articular bleeding, the most common adverse manifestation of these coagulopathies, progress from early synovitis to ultimate end stage, irreversible joint damage [1], unless the frequency and severity of bleeding episodes can be curtailed. Haemophilic haemarthroses are associated with acute pain during bleeding episodes and Correspondence: Craig M. Kessler, MD, Division of Hematology/Oncology, Georgetown University Medical Center, Hemophilia Treatment Center and Coagulation Laboratory, Lombardi Comprehensive Cancer Center, 3800 Reservoir Road, NW, Washington, DC 20007-2197, USA. Tel.: 202 687 8676; fax: +202 687 1437; e-mail: [email protected] Accepted after revision 26 July 2014 © 2014 John Wiley & Sons Ltd

Keywords: adult, analgesics, coping, haemophilia, pain, paediatric

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T. J. HUMPHRIES and C. M. KESSLER

(RA) and sickle cell disease (SCD)], management of chronic pain in haemophilia has been evaluated in only a few robust clinical trials, and only recently there have been attempts to develop age-appropriate and standardized pain scoring systems to expedite the evaluation of pain management in this patient population [12]. This review discusses the published literature relevant to the treatment of chronic pain in haemophilia and other disease states and identifies knowledge gaps pertinent to its management.

6000

5000

Search hits (n)

2

Osteoarthritis Rheumatoid arthritis Sickle cell disease Hemophilia

4875

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3000

2756

2000 1160

Materials and methods

1000 452

395 126

Strategy The successful management and treatment of chronic joint pain in haemophilia have been impeded by the relative dearth of adequately powered, randomized, controlled trials focusing specifically on pain. This is in contrast to the wealth of data on such cognate disease states as OA, RA and SCD [13,14]. To identify the literature devoted to disease states complicated by chronic joint pain, Boolean searches of the ClinicalTrials.gov database were conducted using the search terms ‘pain’ and ‘hemophilia’ (search date, June 20, 2014). Another search on June 20, 2014, combined the term ‘pain’ with ‘osteoarthritis’, ‘rheumatoid arthritis’ and ‘sickle cell’. PubMed/Medline and EMBASE were searched on June 20, 2014, using the same search terms and the following limits: humans; clinical trial; meta-analysis; practice guideline; randomized controlled trial; case reports; classical article; clinical conference; clinical trial, phase 1; clinical trial, phase 2; clinical trial, phase 3; clinical trial, phase 4; comparative study; congresses; consensus development conference; consensus development conference, NIH; controlled clinical trial; electronic supplementary materials; multicentre study; English language; all adult: 19 + years.

Results The ClinicalTrials.gov searches identified far more studies for pain related to OA (n = 1160 studies), RA (n = 395 studies), and SCD (n = 126 studies) than for haemophilia-related pain (n = 24 studies). A similar ratio was apparent in PubMed and EMBASE, with OA (n = 4875), RA (n = 2756) and SCD (n = 452) articles outnumbering haemophilia articles (n = 229). Figure 1 provides a breakdown of the number of studies of individual drugs/drug classes by indication.

How pain is managed and treated in other disease states Guidelines. The published literature has enabled an evidenced-based approach to the development of Haemophilia (2014), 1--11

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229

24

ClinicalTrials.gov

PubMed

Fig. 1. Search results by indication.

treatment guidelines for the management of pain in OA [15–17], RA [18,19] and SCD [20]. Intuitively, it may seem that many of the methods and guidelines developed for these other conditions could be extrapolated to pain management for haemophilic arthropathy; however, the unique haemorrhagic tendencies of haemophilia, potentially exacerbated by the antiplatelet aggregation, drug–drug interactions and pharmacologic effects of some of the most common and efficacious medications for the other diseases, cannot be ignored. Table 1 summarizes key advantages and disadvantages of several classes of analgesic medications administered to patients with OA, RA, SCD and haemophilia. Efficacy. Osteoarthritis: An indirect, but imperfect, approach to examining the efficacy of analgesic pharmacotherapies administered to patients with haemophilia in the absence of evidence-based data and large clinical studies is to extrapolate observations from the more comprehensive findings generated for the same medications evaluated in individuals with OA and RA. Based on the available data, American College of Rheumatology 2012 guidelines conditionally recommend acetaminophen, oral NSAIDs and tramadol as initial therapy for OA of the knee or hip, and strong opioids in patients who do not respond to initial therapy and are either unwilling or unable to undergo joint replacement [21]. However, citing inconclusive evidence, 2013 guidelines issued by the American Academy of Orthopaedic Surgeons do not recommend for or against use of acetaminophen or opioids in patients with knee OA [22]. The efficacy of OA therapies in reducing pain have been compared by calculating effect size, which is defined as the standard mean difference between treatment groups. The 2010 update of the Osteoarthritis Research Society International (OARSI) guidelines for the management of OA-related pain in the knees or © 2014 John Wiley & Sons Ltd

PAIN MANAGEMENT IN HAEMOPHILIA

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Table 1. Summary of advantages and disadvantages of currently available analgesics. Drug/Class Acetaminophen [23] NSAIDs/COX-2 inhibitors [23]

Tramadol (weak opioid/SNRIs)

Strong opioids

Advantages

Disadvantages

• • •

Generally well tolerated



Serious adverse events (e.g. cardiovascular events) less frequent in younger patients [37]



More effective than NSAIDs/COX-2 inhibitors for analgesia [24]



SNRI mechanism imposes dose ceiling on products [48] and may also induce qualitative platelet function abnormalities



May have less potential for abuse and addiction compared with strong opioids [78]



Caution must be used during administration with other serotonergic drugs, digoxin or warfarin [48]

• • •

Most effective oral analgesics available [23]



Associated with potentially serious adverse events, including

May be effective as part of combination products/regimens Provide small to moderate analgesic and anti-inflammatory effects

• • •

Questionable efficacy as monotherapy in inflammatory disease Causes liver function abnormalities at therapeutic doses Associated with systemic adverse events, including o o o o

Available in short-acting and long-acting formulations

o o o o

Availability in multiple dosing forms (e.g. oral and intravenous) allows for smooth transition from inpatient to outpatient analgesia [79]

Gastrointestinal upset Gastric and systemic bleeding and easy bruising Nephrotoxicity Possible increased cardiovascular/ cerebrovascular ischaemia risk

Respiratory depression Constipation Nausea and vomiting Sedation [23]



Risk of abuse or physical and psychological dependence/addiction [47]



No anti-inflammatory properties

COX-2, cyclo-oxygenase 2; NSAID, non-steroidal anti-inflammatory drug; SNRI, serotonin-norepinephrine reuptake inhibitor.

hips have defined effect sizes for pain relief of 0.14 for acetaminophen, 0.29 for oral non-steroidal antiinflammatory drugs (NSAIDs), 0.44 for cyclo-oxygenase (COX)-2 inhibitors and 0.78 for opioids [23]. Effect sizes for the dual weak opioid/serotonin-norepinephrine reuptake inhibitor tramadol extended release (ER) and tramadol/paracetamol combination products (usually 0.40–0.60) have generally been higher than those for NSAIDs but lower than those for strong opioids [24]. As defined, 0.20 is the minimum threshold for a clinically meaningful effect size for pain reduction [23], which implies that at conventional and recommended doses, acetaminophen monotherapy is not effective in patients with OA. The threshold for a moderate clinical effect on pain reduction is 0.50, indicating that the recommended dosing levels for NSAIDs and COX-2 inhibitors provide small to moderate analgesic efficacy. Only the effect size for an opioid approaches the threshold for a robust treatment effect (≥80) [23]. Nonetheless, despite evidence of efficacy, 2014 OARSI guidelines for non-surgical management of knee OA were uncertain regarding whether opioids are an appropriate long-term therapy because of concerns about adverse events [25]. Rheumatoid arthritis: Pain management in RA relies primarily on NSAIDs and corticosteroids [26], although augmentation strategies with opioids and acetaminophen have been examined. A large, randomized, placebo-controlled, double-blind trial of 277 patients with RA indicated that adjunctive tramadol 37.5 mg/acetaminophen 325 mg three times daily for 1 week provided significant improvement in daily pain © 2014 John Wiley & Sons Ltd

relief scores (P = 0.037) and perceived pain intensity (P = 0.018) compared with placebo [27]. There was no improvement in overall physical performance, but the study may not have been of sufficient duration to detect significant changes in this variable. The rationale for NSAID use in the RA population is that they provide additional control of inflammation beyond that provided by disease-modifying antirheumatic drugs (DMARDs) alone, particularly early in treatment. Early NSAID/DMARD combination treatment has been associated with an increased likelihood of remission [28]. Sickle cell disease: US and European guidelines for chronic pain management (joint and/or systemic) in SCD appears to mirror OA guidelines in their reliance on acetaminophen, NSAIDs and weak opioids for mild-to-moderate pain, with strong opioids being reserved for adult patients with severe pain [20,29]. However, the severe acute pain events in SCD vasoocclusive crises are typically generalized and require intensive pain management with parenterally administered (intravenous, intramuscular, or subcutaneous) or patient-controlled opioid analgesics (PCA) [20,29]. There is consistent evidence from randomized controlled studies that PCA provides adequate pain relief with substantially lower overall morphine consumption in patients with SCD and vaso-occlusive crises [30,31]. However, this scenario is not directly pertinent to the haemophilia population, in which the reversal of acute pain is targeted predominantly to a single affected joint and can be achieved more effectively and rapidly by administration of clotting factor replacement therapies. Haemophilia (2014), 1--11

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T. J. HUMPHRIES and C. M. KESSLER

Safety. Acetaminophen has good overall tolerability but may cause liver enzyme elevations and significant hepatic dysfunction in healthy individuals at doses >4 g day 1 [32], making it extremely difficult to titrate the dose sufficiently to promote better outcomes in patients with severe pain. Regarding NSAID use, OARSI guidelines recommend that NSAIDs be administered at the lowest effective dose for the shortest duration of time because of their well-known doseand duration-related association with gastrointestinal and cardiovascular adverse events (AEs; Table 1) [15,16]. The risk of NSAID-related bleeding complications is approximately 2-fold higher in patients with RA compared with OA because of the frequent concurrent use among RA patients of corticosteroids [26], which are known to increase the risk of bleeding associated with NSAIDs [33]. The bleeding propensity in haemophilia renders NSAIDs generally contraindicated for haemarthroses [34], and National Hemophilia Foundation guidelines state that COX-2 inhibitors should be used with caution in patients with haemophilia because of the risks of bleeding events, heart attack and stroke [35]. However, the risk of cardiovascular events with COX-2 inhibitors is associated primarily with long-term use (i.e. ≥180 days) [36] and increases with age [37], suggesting a reasonable therapeutic window for short-term use (12 years abused prescription analgesics during their lifetime, and 2% engaged in non-medical use of oxycodone [39]. Research suggests that vigilant adherence monitoring in patients prescribed opioids can reduce the risk of abuse by approximately 50% [40]. In reality, however, neither addiction nor physical dependence are common when these agents are administered for short periods of time for physical pain events [41,42]. Development of dependence or addiction becomes a problem with prolonged oral opioid administration [42]. A variety of screening tools are available to help assess the potential risk of opioid abuse (Table 2) [43], and several expert panels have developed strategies for screening for risk of abuse, monitoring treatment adherence and addressing misuse if it occurs [44,45]. A systematic review of the literature identified nine basic strategies for predicting, preventing and identifying opioid abuse, including appropriate patient medical assessment, pretreatment screening for opioid risk, treatment agreements/contracts, careful opioid selection and titration, implementation of a dosage ceiling for most patients, use of tamper-resistant opioids, compliance monitoring and

Table 2. Screening tools for opioid abuse [43]. Screening tool Atluri screening tool

Diagnosis, intractability, risk and efficacy (DIRE)

Opioid Risk Tool (ORT)

Screener and opioid Assessment for patients with pain–revised (SOAPP-R) Screening instrument for substance abuse potential (SISAP)

Screening tool for addiction risk (STAR)

Haemophilia (2014), 1--11

Description



Clinician-administered assessment for detecting questionable opioid use in patients with chronic pain



Potential for abuse rated on 6 criteria (opioids, opioid overuse, other substance abuse, low functional status, potentially unclear pain aetiology, exaggeration of pain level and severity)

• •

Higher scores indicate possible abuse; score of 4 indicates risk of abuse

• • •

Risk category subdivided into psychological, chemical health, reliability and social support



Scores 8 indicate high risk

• • • • •

Patient-completed 14-item questionnaire to assess abuse potential before opioids are started



Risk of abuse is based on the patient responses to questions regarding drinking in typical day and typical week, use of marijuana, cigarette smoking and age



Patient-completed 14-item yes/no questionnaire for assessing abuse risk in patients with chronic pain



Questions encompass cigarette, alcohol and drug use; family history of drug or alcohol abuse; pain clinic and emergency department visits; and feelings of depression, anxiety and altered mood

Clinician-rated scale to predict patient compliance with and efficacy of long-term opioid treatment based on four categories (diagnosis, intractability, risk, efficacy) Scores

Managing chronic pain in adults with haemophilia: current status and call to action.

Haemophilic arthroses are associated with acute pain during bleeding episodes and with chronic pain caused by arthritic complications of repeated blee...
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