How does pain in the area of a tendon develop in the first place? Analysis of current evidence in the cellular cause of tendon pain
November 6, 2023
Inflammation or degeneration?
In the past, chronic tendon pain was thought to be due to inflammation. However, chronically painful tendons do not show signs of inflammation. This should not be confused with acute tendonitis, which also results in pain. However, in recent studies, there is evidence that inflammatory cytokines and mediators such as interleukins or substance P contribute to tendon disease. Likewise, diverse immune cells such as mast cells, macrophages, and lymphocytes play an important role in the initiation and regulation of tendon disease.(1)
Tendon degeneration diagnosed by MRI or ultrasound is often painless.(2) This means that not every tendon with degenerative changes results in pain. Where then does the pain come from if it does not correlate with the extent of degeneration?
The importance of neurotransmitter and metabolic factors for tendon pain
Neurotransmitters can also cause pain in tendons. In tendinopathies, lactate is twice as high as in the control group. Lactate is produced in the anaerobic fermentation of sugars and is often elevated in mitochondrial diseases. Thus, this supports our hypothesis that mitochondrial function is important in tendon diseases.
Furthermore, patients with chronic Achilles tendinopathy and patellar tendinopathy show increased levels of the neurotransmitter glutamate.2 The increased levels of glutamate sensitize nerve fibers and lead to increased pain. Particularly in fluoroquinolone-induced tendon pain, dysregulation of the gabaergic/glutamergic nervous system could be a potential cause of pain. This hypothesis is supported by the fact that some medications for nerve pain that act on glutamate result in significant tendon pain reduction in some affected individuals. Is the pain after fluoroquinolone administration similar to the clinical picture of CRPS, in which an initial injury leads to severe nerve pain in the course of the disease? The short-term efficacy of those drugs gives us at least an indication that those two neurotransmitters are important in chronically painful tendons after fluoroquinolone administration.
Substance P is another interesting neurotransmitter and neuromodulator in relation to tendon pain. It is found in the small, unmyelinated nerve fibers in the tendon. These sensory nerve fibers transmit pain to the spinal cord. Elevated levels of substance P correlate with pain in rotator cuff disorders, aswell as tennis and golfer’s elbow (medial and lateral epicondylopathy).(2)
Neovascularization
As mentioned above, tendinopathies are often clinically silent, i.e., painless. The transition to a symptomatic tendinopathy is histologically characterized by the invasion of blood vessels (neovascularization) followed by nerve proliferation as well as an increased glutamate level.(3)
So how does this nonfunctional vascularization occur? As described, lactate is elevated in degenerative tendons. Due to the anaerobic conditions, the transcription factor HIF is induced, which leads to the expression of the growth factor vascular endothelial growth factor (VEGF), a growth factor that is essential for the formation of blood vessels. However, VEGF can also upregulate matrix metalloproteinases (MMPs), again leading to degeneration of extracellular matrix.(3) Likewise, VEGF leads to neovascularization in tendons, with the aforementioned nociceptors also proliferating with blood vessels.
New blood vessel formation occurs in painful tendons, which can be confirmed with Doppler ultrasound. (3,4) Thus, there is an association of chronically painful, degeneratively altered tendons with the presence of neovascularization.(3)
However, neovascularization is also sometimes present in nonpainful tendons.(5) So is it not the primary cause of chronic tendon pain after all?
With regard to fluoroquinolone-associated tendinopathies, it is interesting to see that many patients do not show neovascularization in Doppler ultrasound after fluoroquinolone administration, but still have severe pain.
Changes in the paratendinous tissue
Time and again we see MRI reports from FQAD patients who report healthy tendons but inflammation of the surrounding structures. As you may know from the well-known tendonitis of the hand, such changes are very painful, often more painful than degenerative changes of the tendon itself. We know from pain research that pain does not correlate with the extent of physical damage. Often harmless pathologies (lumbago, tense back muscles) are extremely painful and degenerative changes such as a herniated disc are asymptomatic.
Why the chronic inflammation of bursae and tendon sheaths (paratendinitis) occurs after fluoroquinolone administration is as yet unclear. However, it is a potential cause of chronic tendon pain in FQAD patients.
Overview of potential causes of pain in tendon area
To briefly recap everything discussed, here is an overview of the potential causes of tendon pain in FQAD patients:
Acute pain:
- Acute inflammation (tendinitis)
- Symptoms: redness, swelling, hyperthermia
- Diagnostics: classic signs of inflammation; MRI and ultrasound
- Therapy: RICE – Rest, Ice, Compression, Elevation; acute inflammation inhibition
(Partial) rupture:
- Symptome: Plötzliche Schmerzen mit Funktionseinschränkung
- Diagnostik: MRT, teilweise Ultraschall
- Therapie: Regenerative Medizin (z.B. PRP), eventuell operativ
Chronic Pain
- Degeneration with neovascularization and sprouting nociceptors
- Symptoms: chronic pain, possible thickening of the tendon, no signs of inflammation
- Diagnostics: Detectable by Doppler ultrasound
- Therapy: Pacing, very gentle professional physiotherapy, regenerative medicine, shock wave therapy
- Interaction with the central and peripheral nervous system, altered neurotransmitters
- Symptoms: chronic pain, no visible change, without findings in imaging such as MRI or ultrasound
- Diagnosis: possibly allodynia: pain sensation triggered by stimuli that usually do not cause pain, such as light touches on the skin in the area of the tendons as an indication of central sensitization
- Therapy: Pain Reprocessing Therapy, neural therapy, possibly medication, Mindfulness-based Pain Management (MBPM)
- Low grade inflammation associated with overactive immune cells such as mast cells.
- Symptoms: chronic pain
- Diagnostics not detectable in any imaging.
- Therapy: long-term anti-inflammation (e.g. regular cryo/cold therapy, dietary changes), pacing.
Paratendinitis
- Symptoms: Sometimes severe pain in the area of a bursa or tendon sheath.
- Diagnostics: MRI and ultrasound detectable inflammation of surrounding structures such
as persons, tendon sheaths, etc. - Therapy: long-term anti-inflammation, pacing
Conclusion
Understanding for affected individuals that degeneration of tendon tissue (collagen) is unlikely to be the cause of chronic pain is difficult. As described, degenerative tendons are often asymptomatic (up to 59% in studies). The same is true for other degenerative changes such as herniated discs but also diseases such as osteoarthritis.(5) Pain does not correlate with damage. Only when neovascularization is present do degeneratively altered tendons appear to cause pain. This rarely applies to FQAD patients in my experience.
An important question to ask is why are there people with degenerative altered tendons/tissues who have no symptoms and others with the same findings who suffer from very severe pain?
Current pain research suggests that unless there is a clear pathology such as acute inflammation or a compressed nerve, chronic pain has more to do with the nervous system than degenerative tissue. New therapeutic approaches such as Pain Reprocessing Therapy (PRT), which often have a better success rate than conventional therapeutic approaches,6 confirm this thesis and hold hope for patients with chronic pain.
For more on fluoroquinolone-induced tendon pain therapy, see the next article.
Written by: Marco Karrer
Many thanks for their cooperation: Andrea Gall (spelling), Ferdinand Dirsch (SEO, additions, translation into English), Michael Rosar (content, simplifications), Patrick Horisberger (content, simplifications),
First publication: 28.05.2023
Last update 15.01.2023
First Publication: 28.05.2023
Source:
- Mitochondrial Dysfunction and potential mitochondrial protectant treatments in Tendinopathy,
Xueying Zhan et al. 2021 DOI: 10.1111/nyas.14599 - Biology of tendon injury: healing, modeling and remodeling P. Sharma and N. Maffuli; 2006
- Pathogenesis of tendinopathies: inflammation or degeneration? Michele Abate et al.
- Ohberg L, Lorentzon R, Alfredson H: Neovascularisation in Achilles tendons with painful tendinosis but not in normal tendons: an ultrasonographic investigation. Knee Surg Sports Traumatol Arthrosc 2001, 9:233-238.
- Tendinopathy: Is Imaging Telling Us the Entire Story? Sean I. Docking, Chin Chin OOI, David Connel
- Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain: A Randomized Clinical Trial, Yoni K Ashar, Alan Gordon, Howard Schubiner
