Hemophilia is a chromosomal disorder affecting coagulation that is characterized by spontaneous bleeding.1 The disorder affects approximately 1 in every 5,000 males. Hemophilia can be classified as a deficiency in clotting factor VIII (ie, hemophilia A), which is more common, or as a deficiency in clotting factor IX (ie, hemophilia B).
The goal of hemophilia management is to prevent spontaneous bleeding episodes, which is achieved by replacing the deficient clotting factor using blood products referred to as clotting factor concentrates.1,2 Joints are the most common location of acute hemorrhagic events, with approximately 90% of bleeds occurring in a joint.3 Joint bleeding, also referred to as hemarthrosis, can result in chronic pain, which is estimated to affect approximately 40% to 70% of persons with hemophilia (PwH).4
Acute hemarthrosis episodes are also a notable source of acute pain, and PwH may not be able to readily differentiate between acute and chronic pain.2 Acute hemarthrosis pain is managed with on-demand administration of clotting factors, which stop bleeding and consequently alleviate pain. Over time, hemarthrosis causes synovial inflammation, which evolves into hemophilic arthropathy, a condition characterized by chronic bone and joint damage. Chronic inflammation and hemophilic arthropathy are significant sources of chronic pain in PwH, affecting 90% of patients with severe hemophilia.2,5 Joints that are most affected by chronic pain include the elbow, knee, and ankle.6 Chronic pain from hemophilic arthropathy is an issue brought to the forefront over the past century, as the lifespans of PwH have increased due to the availability of safe blood-product treatments.7
Patients with hemophilia experiencing pain from hemophilic synovitis and arthropathy have reported limitations in daily activities, increased disability, and decreased quality of life.4,8 Like many chronic pain conditions, PwH report that pain negatively affects mental health. Despite the negative effects of chronic pain and the high prevalence in PwH, surveys have shown that PwH typically do not receive adequate pain control.The body of available evidence surrounding the optimal strategy for managing pain associated with hemophilic synovitis and arthropathy is scarce. However, recent guideline recommendations have provided insight into management strategies while considering treatment challenges specific to PwH.
Pathophysiology of Chronic Pain and Hemophilic Arthropathy
While the pathophysiology of chronic pain in PwH is not completely known, iron deposition from the blood into the synovium is thought to play a key role.7,8 When hemarthrosis occurs, the synovium works to remove blood from the joint, causing iron to build up.2 Iron deposition in the synovium provokes an inflammatory response, which can resolve within several weeks.2,3 However, chronic and subclinical hemorrhages prevent resolution and lead to chronic synovitis and eventually synovium hypertrophy. Chronic inflammation and hypertrophy result in increased vasculature and predispose the joint to further bleeding.6 This initiates a cycle of bleeding and inflammation, and the change in the vasculature is likely not reversible. The cytokines produced from this inflammatory process cause cartilage and bone destruction, which is the cardinal sign of hemophilic arthropathy. Furthermore, direct blood exposure is theorized to lead to bone and cartilage degradation and cause chondrocyte apoptosis. Irreversible damage to the joint may result from as little as 2 to 3 bleeding episodes.
Hemophilic arthropathy is not considered age-related or inflammatory arthritis, like osteoarthritis or rheumatoid arthritis, respectively; however, the pathophysiology of hemophilic arthropathy shares some similarities with these conditions.9 For example, both rheumatoid arthritis and hemophilic arthropathy involve inflammatory processes and bone resorption. Osteoarthritis also involves cartilage destruction. These similarities may be useful for extrapolating management principles for hemophilic arthropathy.
Pain Assessment Tools for Patients with Hemophilia
The World Federation of Hemophilia (WFH) recommends assessing musculoskeletal and overall health in PwH at least annually. This evaluation should assess joint and muscle structure and function as well as quality of life. Numerous validated scales for PwH are available to assess pain and clinically useful outcomes, such as function, activity level, and quality of life, and the WFH recommends using these when available (Table I).
Additionally, ultrasound and magnetic resonance imaging (MRI) can be utilized to evaluate early changes in joint structure. Plain radiographs can be used to capture late structural changes associated with hemophilic arthropathy. Several scales and scoring tools can be applied to imaging to quantify structural changes, which are outlined in Table I.
The WFH and National Hemophilia Foundation (NHF) recommend screening patients with chronic pain for anxiety and depression, as these conditions can contribute to pain and interfere with achieving optimal outcomes.2,4 Standardized tools for evaluation include the Physicians’ Health Questionnaire 9-item (PHQ-9) scale for depression, Generalized Anxiety Disorder 7-item (GAD-7) scale for anxiety, and the PHQ-4 scale for both depression and anxiety.
Pain Management Principles
Goals of pain management should focus on function and activity.2 In order to achieve these goals, nonpharmacologic interventions should be utilized as part of a comprehensive pain plan. Physical therapy and rehabilitation are recommended for all patients with chronic synovitis and hemophilic arthropathy. These therapies should be continued as part of a pain management regimen regardless of analgesic medication use. Bracing can be used to stabilize the affected joint, along with exercises to maintain joint strength.
Complementary interventions, such as meditation, music therapy, distraction, and mindfulness can also be considered for hemophilic arthropathy, and the WFH recommends including these techniques as part of pain management education.
For synovitis, a procedure referred to as a synovectomy can be utilized if other measures fail to reduce inflammation.2 Additional surgical measures can be considered for patients with hemophilic arthropathy who have failed nonsurgical interventions. These procedures are typically performed by orthopedic specialists.
Non-steroidal anti-inflammatory drugs (NSAIDs) are typically recommended as a non-opioid agent to be used as part of a multimodal analgesic regimen for non-hemophilia conditions.2,4 NSAIDs exert their effects by inhibiting the cyclo-oxygenase (COX)-1 and/or COX-2 pathway. The COX-1 pathway is responsible for producing protective prostaglandins that increase blood flow, as well as mucus and bicarbonate production in the stomach. Inhibition of the COX-1 pathway results in an increased risk of gastrointestinal (GI) bleeding. In contrast, COX-2 is responsible for inflammation, pain, and fever; therefore, inhibition of COX-2 would be desirable for achieving analgesic effects. Bleeding in the GI tract is a well-known adverse effect of non-selective NSAIDs, and the effect is thought to be exacerbated in PwH, given the high predisposition for bleeds. As a result, the NHF and the WFH both recommend that non-selective NSAIDs be avoided in PwH. The NHF and WFH recommend the use of selective COX-2 inhibitors in PwH, as COX-2 inhibitors have a lower risk of platelet inhibition and GI ulceration. For patients with an increased risk of developing a GI ulcer, the NHF suggests considering a gastroprotective agent.
Recommended Analgesic Regimen
Preventing and managing hemarthrosis is integral to pain management, as progression of synovitis and joint damage may worsen pain.2 This is achieved using clotting factor concentrates. Despite optimal use of clotting factor concentrates to control bleeds, pain management using analgesics will often be necessary. The WFH published an updated guideline for the management of hemophilia in 2020. The guideline recommends the use of several analgesic agents in a stepwise scheme, which is outlined in Table II.
This stepwise approach is recommended for both acute and chronic pain episodes. In general, the use of opioids should be avoided whenever possible, given the chronic nature of hemophilia bleeding episodes and potential for addiction with extended use. Pain management specialists should be consulted for patients who require opioid analgesics to ensure adequate monitoring. Pain management plans should be adjusted based on clinical presentation with the goal for the patient to be able to comfortably bear weight.
Aside from this stepwise approach, the WFH recommends the use of selective COX-2 inhibitors in patients with chronic synovitis to reduce inflammation and prevent damage to the joint.2 Celecoxib is the only selective COX-2 inhibitor available in the United States, and is used off-label for chronic pain associated with hemophilia. Typical adult dosing is 200 mg per day given once or twice daily, depending on the indication.12 Doses of up to 400 mg per day have been utilized for certain conditions (eg, rheumatoid arthritis, ankylosing spondylitis, acute pain, and primary dysmenorrhea). The WFH lists meloxicam as a potential COX-2 inhibitor to be used in PwH; however meloxicam exerts its mechanism of action via both COX-1 and COX-2 and carries a black box warning for GI bleeding, ulceration, and perforation.2,13
Application of the CDC’s Opioid Prescribing Guidelines
An estimated 50% to 70% of PwH are prescribed opioids for pain.4 In 2020, the NHF published guidance for applying the Centers for Disease Control and Prevention’s (CDC’s) opioid prescribing guidelines to patients with bleeding disorders, given the unique aspects of this population’s care. The guidance outlines several key recommendations.
Similar to the WFH, the NHF recommends that opioids can be considered when nonpharmacologic interventions and nonopioid agents fail to provide relief and when opioid benefit is expected to outweigh risk.4 Nonpharmacologic interventions and nonopioid agents should be continued in conjunction with opioids, as multimodal treatment has been shown to be more effective than monotherapy.
The NHF suggests the use of short-acting opioids only, which is consistent with the CDC opioid guidelines but differs from the WFH recommendations.4 Short-acting opioids should be used to manage exacerbations and prevent anticipated pain due to activity. Doses should be less than 90 morphine milligram equivalents (MME) per day, with the goal of reducing the total daily dosage to less than 50 MME. It may not be possible to reduce doses to these recommended limits in all patients, especially those on higher doses for extended durations. The decision to reduce opioid dosages should be individualized and take into consideration whether the benefits of reducing the dose outweighs the risk of decreased efficacy.
Opioid Monitoring and Follow-Up
Monitoring for opioid misuse is recommended prior to initiating opioids and for patients prescribed opioids.4 Several risk tools are available to evaluate opioid misuse risk, including the 5-question Opioid Risk Tool (ORT) and the 24 question Screener and Opioid Assessment for Patients with Pain – Revised (SOAPP-R). Additionally, providers should review their Prescription Drug Monitoring Program (PDMP) to establish a patient’s medication history. Regardless of opioid misuse risk or prescribed dose, the NHF recommends that naloxone be prescribed to all patients treated with opioids.
Risks and benefits for opioid therapy should be assessed regularly.4 The NHF recommends assessing patients being managed for chronic pain at every visit. This should ideally occur at least every 3 months, and as early as 1 to 4 weeks after starting opioids or increasing doses. The monitoring process should be transparent to patients, and clinicians should consider outlining indications for discontinuing opioid therapy. When weaning opioids, tapering should be individualized for the patient, and other analgesic modalities should be added or increased to compensate for a possible increase in pain.
Intra-articular injections of corticosteroids, hyaluronic acid, and platelet-rich plasma have been used in osteoarthritis successfully for short-term relief of pain.9 In osteoarthritis, clinical data has shown that corticosteroids and hyaluronic acid may relieve pain for weeks or months, respectively. Additionally, intra-articular injections of mesenchymal stem cells have been utilized in osteoarthritis with promising effect. Given the successful use of intra-articular injections in osteoarthritis, an interest in their use for hemophilic arthropathy has developed. Little data exist specific to the use of intra-articular injections in patients with hemophilia, and no clinical data have examined the use of mesenchymal stem cells in hemophilic arthropathy.
In 2018, Buccheri and colleagues compiled the available literature pertaining to intra-articular injections in PwH and concluded that hyaluronic acid may be beneficial alone or in combination with other drugs for hemophilic arthropathy.9 The effects from hyaluronic acid appear to last for 6 months to 1 year. In studies, hyaluronic acid was administered as 3 to 5 injections given every 1 to 4 weeks with the ability to repeat the administration cycle in 6 to 12 months. To date, no randomized controlled trials have been performed specifically in hemophilia patients.
Likewise, little information is available regarding the use of intra-articular corticosteroids in hemophilia.9 A retrospective review evaluated the use of ultrasound-guided intra-articular corticosteroids for chronic joint pain in patients between March 2012 and January 2016.14 Patients were given intra-articular corticosteroids if they were unable or unwilling to use alternative strategies or oral medications or if they did not respond to other therapies. Injections were administered to either the ankle (n = 14), elbow (n = 13), or knee (n = 18). A total of 84% of patients experienced a > 30% reduction in pain, which was typically within the first 24 hours. Median duration of effect was 8 weeks. Due to the lack of comparative data and high costs, intra-articular corticosteroids have not been widely used in practice and experts do not recommend them as part of standard care.15
Several studies have found benefit with platelet-rich plasma in patients with hemophilia and chronic synovitis.9 However, studies specific to hemophilic arthropathy are generally lacking. Li and colleagues compared the use of intra-articular platelet-rich plasma with hyaluronic acid injections for hemophilic arthropathy affecting the knee in a non-randomized, open-label trial.16 Platelet-rich plasma was administered as a single injection (n = 11) and hyaluronic acid was administered as weekly injections for 5 weeks (n = 11). At 6 months, patients receiving platelet-rich plasma had more significant relief compared to hyaluronic acid in regard to change in visual analogue scale (VAS) score (-2.5 vs. -0.7; P = 0.016), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (-9.0 vs. 2.4; P = 0.047), and physical function score (-130.9 vs. 52.5; P = 0.028).
Although the literature on the use of intra-articular hyaluronic acid and platelet-rich plasma is encouraging, current evidence is limited and has not been incorporated into practice guidelines.
Patients with hemophilia frequently experience chronic pain as a result of chronic synovitis or hemophilic arthropathy, which results from spontaneous and recurrent hemarthrosis.2 While the primary goal should be to prevent and stop bleeding episodes using clotting factor concentrates, irreversible damage can occur from a few episodes. Several key elements should be considered when managing pain in PwH:
- Nonpharmacologic interventions, including physical therapy and rehabilitation, should be used prior to initiating and in conjunction with pharmacologic therapy.2
- Nonselective NSAIDs should be avoided due to increased risk of bleeding. The selective COX-2 inhibitor celecoxib is recommended to reduce inflammation and prevent progressive joint damage.2,4
- A stepwise approach should be implemented when selecting a pharmacologic pain regimen (Table II).2
- Chronic opioid therapy should be avoided, if possible. When utilizing opioid agents, the NHF guideline for implementing the CDC’s opioid recommendations should be utilized to ensure safe and appropriate practices.2,4