To the Editor:

I read with interest the review article by Sharma and Maffulli on “Tendon injury and tendinopathy: healing and repair. (J Bone Joint Surg Am. 2005; 87-A:187-202.)[1]

I would like to supplement their view on the etiology and treatment of tendinopathy.

Ljung et al.[2] showed the existence of a calcitonin-gene related peptide (CGRP)-immunopositive nociceptive C-fiber innervation at the tendon insertions at the lateral as well as the medial epicondyle in patients suffering from epicondylalgia. Their results gave further evidence for a possible neurogenic involvement in overuse tendinopathy.

It is well known that activation of unmyelinated nociceptive sensory neurons through noxious stimuli and subsequent release of neuropeptides such as CGRP from peripheral nociceptive nerve endings results in a nerve- mediated inflammatory response. Beyond its primarily inflammatory character this neurogenic inflammation can be regarded as a mechanism that activates protective responses, thus bringing about a first line of defence to maintain the integrity of the tissue and to contribute to tissue repair.[3]

Interestingly, Ohtori et al.[4] had shown almost complete degeneration of CGRP-immunopositive nociceptive C-fibers following a single application of low-energy shock wave application in rats. Reinnervation occurred 2 weeks after treatment. Takahashi et al.[5] repeated the experiment, comparing the effect of a single low-energy shock wave application with that after two applications (2-week interval). In both groups the number of CGRP-immunopositive C-fibers was significantly less than in the control group until 4 weeks after shock wave application. However, after two applications the amount of regeneration of nerve fibers was far smaller than after a single application even until 42 days after treatment. The authors hypothesized that the initial application of shock waves caused a local liberation of neuropeptides such as CGRP from the nociceptors, a result of (a) unphysiologically, the direct mechanical damage to nociceptive nerve fibers (denervation), and (b) physiologically, the noxious nociceptive irritation. The second application accentuated the pro-trophic neurogenic inflammatory changes and delayed reinnervation.

Recent studies suggested a negative effect of local anesthesia on the clinical outcome after repetitive low-energy shock wave application.[6,7] Local anesthetics are known to block liberation of neuropeptides from nociceptive nerve endings, thus suppressing activation of the protective response essential for tissue regeneration/healing.

In human experiments CGRP released from C-fiber nociceptors induces vasodilation and enhance protein extravasation (= neurogenic inflammation) which is visible on the skin as a flare response surrounding the site of mechanical injury. The pathway of neurogenic vasodilation is organized as an axon reflex. Activation of peripheral C-nociceptors provokes nerve impulses which are conducted centrally. At some branching points of the axonal tree these action potentials may invade peripheral branches in the neighbourhood of the injury, causing the release of vasodilatory neuropeptides, eg. CGRP. The degree of the flare response is commonly evaluated by Laser Doppler Imaging (LDI).[8]

In a recent experiment 20 healthy subjects underwent a single application of 2000 low-energy shock waves to the skin of the lower arm. In a subsequent experiment shock waves were applied after the skin had been covered for 4 hours with an EMLA tape containing local anesthetics. The flare response was evaluated using LDI, 15 minutes after shock wave application. The axon reflex erythema was significantly smaller after EMLA application, with the difference to non-EMLA shock wave application increasing with a rising intensity of shock waves. The experiment clearly showed that low-energy shock wave application was capable of inducing an efferent CGRP-mediated response from afferent nociceptive nerve fibers. Administration of local anesthesia prior to shock wave application effectively inhibited this pro-trophic reaction (Klonschinski and Rompe, personal communication).

Together, neuropeptide involvement of local nocicepting nerve fibers appears to play a key role at least in the pathophysiology of stage 2 insertional tendinopathy,[9] showing minor pathological alterations such as angiofibroblastic degeneration without any structural failure or rupture.

In animal and human experiments, low-energy shock wave application influenced nociceptive nerve fibers. Directly, the repetitive shock wave stimulus lead to a destruction of nociceptive nerve fibers in the focal area with subsequent local liberation of neuropeptides. Reinnervation regularly occurred from 2 to 6 weeks after shock wave application. Indirectly, the repetitive shock wave stimulus resulted in a neuropeptide- induced spreading axon reflex erythema regarded as a direct sign of a CGRP -mediated neurogenic inflammation. Such a neuropeptide-induced inflammation has been shown to be a mechanism activating protective responses, bringing about a first line of defence to maintain the integrity of the tissue and to contribute to tissue repair. Administration of local anesthesia prior to application of low-energy shock waves effectively inhibits the release of neuropeptides from nociceptive nerve endings, thus blocking their pro-trophic efferent function which may promote local tissue healing.

Sincerely yours,

Jan D. Rompe, MD

References

1. Sharma P, Maffulli N. Tendon injury and tendinopathy: healing and repair. J Bone Joint Surg 2005; 87-A:187-202.

2. Ljung BO et al. Neurokinin 1-receptors and sensory neuropeptides in tendon insertions at the medial and lateral epicondyles of the humerus. Studies on tennis elbow and medial epicondylalgia. J Orthop Res 2004; 22:321-327.

3. Herbert MK, Holzer P. Neurogenic inflammation. Pathophysiology and clinical implications. Anasthesiol Intensivmed Notfallmed Schmerzther 2002 ;37:386-394.

4. Ohtori S et al. Shock wave application to rat skin induces degeneration and reinnervation of sensory nerve fibres. Neurosci Lett 2001; 315:57-60.

5. Takahashi N et al. The mechanism of pain relief in extracorporeal shock wave therapy. Presented as a poster at the Annual Meeting of the American Academy of Orthopaedic Surgeons; 2004 Mar 10-14; San Francisco, CA.

6. Labek G et al. Influence of local anesthesia and energy level on the clinical outcome of extracorporeal shock wave treatment of chronic plantar fasciitis. A prospective randomised clinical trial. Z Orthop Ihre Grenzgeb, in press.

7. Rompe JD, Meurer A, Nafe B, Hofmann A, Gerdesmeyer L. Repetitive low-energy shock wave application without local anesthesia is more efficient than repetitive low -energy shock wave application with local anesthesia in the treatment of chronic plantar fasciitis. J Orthop Res, in press.

8. Kramer HH et al. Electrically stimulated axon reflexes are diminished in diabetic small fiber neuropathies. Diabetes 2004; 53:769- 774.

9. Nirschl RP, Ashman ES. Tennis elbow tendinosis (epicondylitis). Instr Course Lect 2004; 53:587-598.