Pain Impact and Management in Individuals With Transfusion-Dependent Thalassaemia

Over the last several decades, there has been significant progress in addressing the main symptoms and related health issues of people with transfusion-dependent thalassemia (TDT). Yet, the problem of pain and how it reduces the quality of life for these patients is often overlooked.

A December 2023 study in the journal Hemoglobin looked at medical data and a Pain Questionnaire to learn about how common and severe pain is among 165 individuals over 10 years old with TDT, also considering their other health problems.

The study found that about 60% of these patients had felt pain in the last month. Women, people with jobs, and those living in cities reported more pain than others. Most patients said they felt pain mainly in their lower back and calves.

Women reported that pain affected their mood. Meanwhile, people between 21-30 years old said that pain greatly hindered their daily activities and enjoyment of life. The study also noticed a link between experiencing pain and having high levels of iron in the blood, severe iron buildup in the liver, and not enough vitamin D.

Another research article from 2022 published in Thalassemia Reports focused on 71 patients (most older than 18 and with TDT), finding that nearly half suffered from daily bodily pain. This study also hinted that less physical activity and more time spent inactive could lead to weaker bones, potentially increasing the intensity of pain for those with thalassemia.

The following interview of Janet Kwiatkowski, MD, MSCE, Director of the Thalassemia Center at Children’s Hospital of Philadelphia, and Rachel Nuss, MD, Haematologist at Children’s Hospital Colorado, Anschutz Medical Campus in Aurora was featured in Hematology Advisor and is reproduced in full:

According to several papers, pain is a complication of thalassemia that is often overlooked.² In your experience and based on the available literature, how common is pain in patients with thalassemia and what are the known or suspected contributing factors?

Dr Kwiatkowski: Pain is increasingly being recognized as a complication of thalassemia and its treatment. In 2010, data from the Thalassemia Clinical Research Network, which comprised several thalassemia centers in North America, were published. In that study, 69% of adolescents and adults reported bodily pain, and 28% had at least moderate pain.⁴ The study by Grewal and colleagues confirmed these findings.²

The cause of pain in individuals with thalassemia is not fully understood and seems to be related to many different factors. Some of these factors include low bone mineral density that can lead to fractures, anemia with increased ineffective red cell production, pockets of extramedullary hematopoiesis that can compress nerves, iron overload, and iron chelation. Increasing age and female sex also correlate with pain, as also seen in the general population. Importantly, chronic pain negatively impacts quality of life in individuals with thalassemia.

Dr Nuss: Arthralgia and low back pain have been reported by 21% and 6%, respectively, of children with TDT.⁵ As people with TDT age, bone pain becomes a more common problem. Pain may also affect those with nontransfusion dependent beta thalassemia but is less well studied. The lower back is the most frequently reported site of pain,^1,2 but hips, knees, and wrists may be affected.

There are many factors that contribute to bone disease in TDT and may contribute to bone pain.⁶

• Bone pain is most often associated with low hemoglobin. If hemoglobin levels are consistently less than 9-9.5 g/dL, marrow expansion ensues, with the development of cortical thinning and osteoporosis. Microfractures are common and can cause pain. Especially in the lumbar spine, vertebral collapse may ensue. Seemingly minor trauma can result in overt fracture of other bones. Spinal deformity manifesting as scoliosis can cause bone pain.

• Transfusional iron overload inhibits bone formation, thus contributing to the development of osteoporosis. Similarly, iron-overload endocrinopathies inhibit bone formation and contribute to osteoporosis. Although osteoporosis is not associated with pain, it incurs a risk for microfracture and overt fractures.⁷

• Iron chelators are prescribed for those with TDT. Side effects include inducing arthropathic changes and arthralgias.

• Luspatercept, a drug that may be prescribed to reduce blood transfusion requirements, has been associated with a side effect of arthralgia.⁸

• Nutritional deficiencies, especially in vitamin D, calcium, and zinc, occur frequently in those with TDT and contribute to the development of osteoporosis and bone thinning, predisposing these individuals to bone fracture and pain.

• Individuals with TDT usually are sedentary which negatively impacts bone health by predisposing to osteopenia and osteoporosis.³ It has been theorized that pain severity may be related to reduced bone mineral density. Pain for those with TDT, as is true for the general population with osteoporosis, is reported to be triggered by prolonged standing or lifting heavy objects.

• Individuals with TDT are also predisposed to autoinflammatory diseases such as rheumatoid arthritis, which is associated with pain. As patients live longer, pain associated with osteoarthritis may ensue.

Why has pain in thalassemia been underrecognized, and what can clinicians do to improve screening for pain in this patient population?

Dr Kwiatkowski: Historically, thalassemia care has focused on optimizing transfusions and iron chelation therapy and managing complications such as hypothyroidism, diabetes, and heart failure. With improved clinical care in thalassemia, patients are now living longer, and pain is increasingly being recognized as a common complaint. Pain may be underrecognized if it is not reported by patients or if healthcare providers do not ask about it. Thus, it is important that healthcare providers regularly ask patients about pain and possible contributing factors.

What are the recommended treatment approaches for the common causes of pain in these patients? 

Dr Nuss: A lifestyle with adequate activity, no smoking, and limited alcohol is recommended. As indicated above, it is critical to maintain an adequate hemoglobin. Avoidance of iron overload resulting in endocrinologic issues is recommended. Optimal dosing of chelators and monitoring for toxicity is indicated. Good nutrition is advised, with supplementation — especially for calcium, vitamin D, and zinc — if deficiency is found on routine laboratory testing.⁹

Routinely monitoring bone mineral density, starting in adolescence, is essential, with treatment to follow as indicated. If a rheumatologic disease such as rheumatoid arthritis is diagnosed, disease-directed therapy is indicated. If osteoporosis is identified, bisphosphonates may be indicated. Anti-inflammatory medications may be helpful. Only brief courses of opiates should be considered.

When should patients with thalassemia be referred to other specialists, such as physical therapists or mental health clinicians, to help reduce pain and improve coping with pain?   

Dr Kwiatkowski: Reduced physical activity has been shown to contribute to pain, and referral to a physical therapist can be helpful. Exercise such as daily walks and light resistance training can be very helpful. Referral to an endocrinologist is indicated for management of osteoporosis and endocrinopathies.

Chronic pain may contribute to anxiety and depression, which in turn can worsen chronic pain symptoms. Referral to a mental health specialist can be very helpful for patients. Referral to a pain specialist, especially for chronic, moderate to severe pain also should be considered.

Dr Nuss: Physical therapy is a wonderful option for bone pain that interferes with mobility or quality of life. Braces or other supportive devices may be useful. Massage, acupuncture, or acupressure may be of benefit as well.

It has been reported that a greater number of painful sites and increased visits for pain correlate with depression and anxiety in those with TDT.¹⁰ Referral for mental health support would certainly be indicated for those situations. Antidepressants may be helpful but are associated with increased risk of developing osteoporosis. Learning relaxation techniques, guided imagery, or biofeedback may be helpful.

To better manage pain in patients with thalassemia, what are some remaining gaps that warrant further attention?

Dr Kwiatkowski: Despite the realization that pain is common in individuals with thalassemia, the etiology of pain in this patient population remains poorly understood. Larger studies that assess potential contributing factors to pain and directed treatments are needed. Education of patients and healthcare providers about this important issue is paramount.

Dr Nuss: Bone pain is a common, although not well-researched, focus in TDT. TDT is a very complex disease warranting federally funded clinical and research centers who collaborate to advance understanding and treatment of bone disease and pain as well as the many other complications of TDT.