BACKGROUND Achilles tendinopathy-pain in the Achilles tendon-is a common and often long-lasting condition that limits physical activity and performance, and also affects work capacity and quality of life. The pain is localized either to the mid- portion of the tendon or at its insertion into the calcaneus. Although individually tailored exercise is the first-line treatment, symptoms persist in many patients, highlighting the need for adjunctive therapies.

AIM This interdisciplinary and innovative research project aims to evaluate the effect of shockwave therapy in Achilles tendinopathy, both in cases where the pain is located in the mid-portion of the tendon and where it is situated at the tendon's insertion. In addition to assessing effects on pain and function, the study will examine the impact on calcifications, neovascularization (evaluated via Doppler ultrasound), and-uniquely-systemic immunological effects, with a focus on NK cells in the blood, an area that remains largely unexplored. METHOD This is a randomized controlled trial (RCT) with four arms, including 200 patients divided into two groups based on pain location. Half of the participants will receive adjunctive shockwave therapy in six sessions, in addition to exercise following the protocol by Silbernagel et al. The primary outcome measure is self-reported pain assessed using the Numeric Rating Scale (NRS) 0-10 at 12 months.

Secondary outcomes include function, assessed through patient-reported outcomes (Victorian Institute of Sport Assessment-Achilles Swedish version, VISA-AS), calf muscle strength and endurance, and jumping ability using a validated test battery. Neovascularization and tendon cross-sectional area will be evaluated using ultrasound/Doppler.

In a sub-cohort, immune cell composition in blood will be analyzed using flow cytometry before and after treatment. For patients undergoing surgery, tissue samples will also be collected for cellular composition analysis.

SIGNIFICANCE This project has the potential to improve treatment strategies, reduce the need for surgery, and generate entirely new knowledge about the relationship between local tissue pathology and systemic immune responses.

Pain in the Achilles tendon, Achilles tendinopathy, is a common musculoskeletal condition affecting adults of all ages. The condition is characterized by localized pain and swelling in the Achilles tendon, particularly during tendon loading, functional limitations, and, in chronic cases, pathological neovascularization. Achilles tendinopathy is considered a typical overuse injury, and the diagnosis is made clinically. The incidence is reported to be 2/1000 per year, which would mean that approximately 1,400 individuals are affected each year in the Gothenburg area alone. A recent study from the United Kingdom has also shown that the typical patient is not physically active-as many clinical guidelines are designed for-but rather between 50 and 60 years old, has a high BMI, and often presents with comorbidities such as hypertension and diabetes. This highlights the need to review current clinical guidelines and evaluate the evidence for alternative treatments.

The pain is usually load-related and located either in the midportion of the Achilles tendon or at its insertion on the calcaneus. The condition is often long-lasting despite adequate treatment, and in addition to limiting physical activity, it can also affect work ability and quality of life. Non-operative treatment with heel-raise exercises and load management-appropriately dosed exercise-is the first-line standard, although long-standing or treatment-resistant cases may require adjunct therapies. Among these, extracorporeal shockwave therapy (ESWT), administered either radially (rESWT) or focally (fESWT), has emerged as a promising intervention in several studies, although it has been questioned in others. Shockwave therapy targets both pain relief and restoration of function, but its effects on pain, function, tendon morphology, and immune cell levels remain largely unexplored.

Recent systematic reviews have emphasized the need for higher-quality studies to determine whether adding shockwave therapy is beneficial for patients with Achilles tendinopathy. Evidence remains limited regarding whether shockwave therapy provides comparable pain relief for midportion versus insertional pain. Furthermore, it is unclear whether shockwave therapy must be combined with heel-raise exercises and load management or whether it can function as a standalone treatment.

Doppler ultrasound is commonly used to quantify neovascularization in the tendon. Some studies have shown that shockwave therapy induces transient increases in neovascularization that coincide with clinical improvement, while others have found no effect on neovascularization. Tendon thickness and the effect of shockwave therapy on intratendinous calcifications have also been investigated, but no consensus has been reached. Much of this research area remains unexplored due to the small number of studies and limited sample sizes.

Despite a growing evidence base suggesting that appropriately dosed exercise combined with shockwave therapy may be beneficial for tendon injuries, several areas remain under-investigated. Notably, no publications have been found on whether the micro-injuries potentially induced by shockwave therapy may cause systemic effects and thereby alter immune cell levels. Unpublished data from our research group have shown that early loading of a ruptured Achilles tendon increases circulating NK-cell levels, but whether this also applies to a painful tendon with potential tendinosis changes is unknown.

The aim of this project is to evaluate two different treatment methods for patients with Achilles tendinopathy-appropriately dosed exercise alone or appropriately dosed exercise combined with shockwave therapy-with a focus on:

Pain and muscle function

Neovascularization and calcifications in the tendon

Systemic changes in immune cell composition in the blood, with a focus on NK cells and CD8+ T cells

Hypotheses Appropriately dosed exercise combined with shockwave therapy leads to reduced pain and improved function compared with appropriately dosed exercise alone.

Appropriately dosed exercise combined with shockwave therapy reduces neovascularization and calcifications in the tendon.

Appropriately dosed exercise combined with shockwave therapy induces micro-injuries in the tendon that generate a systemic immune response (higher levels of NK cells and CD8+ T cells).

Appropriately dosed exercise combined with shockwave therapy has similar effects regardless of whether the pain is located in the midportion of the Achilles tendon or at its insertion.

Significance This project has the potential to improve the treatment of Achilles tendinopathy by identifying which patients benefit from shockwave therapy and by increasing the understanding of the biological effects of different treatment methods. The results may contribute to more individualized treatment and reduce the need for surgical interventions.

Inclusion Criteria:

• Women and men over 18 years of age who seek care for load-related pain in the midportion of the Achilles tendon or at the Achilles tendon insertion at a Physiotherapy Clinic in Primary Care, at the Physiotherapy Department at Sahlgrenska University Hospital/Mölndal, or at the Orthopedic Department at Sahlgrenska University Hospital/Mölndal.
• Symptoms must have been present for one month or longer.
• Symptoms may be present in one or both Achilles tendons.

Exclusion Criteria:

• Unwillingness to receive shockwave therapy.
• Previous shockwave therapy for Achilles tendon pain within the past year.
• Neurological disease, significant cardiac conditions, increased bleeding tendency, treatment with anticoagulant medication, pregnancy, or presence of a tumor in the foot.
• Corticosteroid injection in the foot within the past six months.
• Reduced sensation, acute inflammation, or any wound around the heel.
• Inability to understand or speak Swedish.