In 1952, Dr. Michel Pistor, a generalist practicing in rural France, administered 10 ml of procaine intravenously in an attempt to abort an acute asthmatic attack in a patient. While the treatment did not ameliorate the patient's respiratory status, upon follow-up, the patient reported a significant improvement in his impaired hearing. Soon thereafter, Dr. Pistor began experimenting with superficial injections of procaine around the ear of hearing-impaired patients and experienced some success. Soon his practice was full of hearing-impaired patients seeking treatment. His results were mixed, however. Many of these patients saw improvement in seemingly unrelated concomitant conditions, such as eczema of the auditory canal and TMJ pain. Additionally, patients reported improvement with tinnitus, which can be related to hearing impairment.¹

Dr. Pistor continued experimenting with superficial injections of procaine for the treatment of a spectrum of disorders, and on June 4th of 1958, he published an article describing his clinical success with this novel procedure in which he stated, "the action on the tissues originating from the mesoderm is so extensive that these treatments should be called mesotherapy" (author's translation). This was the first time the term "mesotherapy" appeared in print. Dr. Pistor described mesotherapy as, "smallest dose, infrequently, in the correct location."²

The first international conference on mesotherapy took place in 1976, which was also the year when mesotherapy was first used in in-patient settings in France. In 1981, Dr. Jacques LeCoz introduced mesotherapy into the orthopedic clinic at the Institute Nationale du Sports (National Institute of Sports) in Paris. In 1987, the French Academy of Medicine officially recognized mesotherapy as a legitimate treatment modality within conventional medicine.³

Currently, in France, although still viewed as experimental and unproven, mesotherapy is recognized as a legitimate treatment modality by the French Academy of Medicine and is reimbursable by their national social security medical coverage. It has been integrated into France's largest sports medicine facility⁴ and is practiced in a number of pain management centers in France⁵ as well as in North Africa.⁶ Apart from the French Society of Mesotherapy, some of the more established national mesotherapy associations or societies are in Algeria, Argentina, Belgium, Brazil, Colombia, Great Britain, Germany, Greece, Israel, Italy, Mexico, Portugal, Russia, Switzerland, Spain, Tunisia, Turkey, and Venezuela. Cosmetic mesotherapy is currently exploding with popularity in Asia, with new national associations and societies being formed every year.

Basic Tenets of Mesotherapy
Mesotherapy is characterized by its unique styles of injection: various superficial injections, using specialized short needles and specific techniques, into the epidermis, dermis, and hypodermis directly over the sites of the affected structures.⁷ Dr. Pistor described this treatment as mesotherapy. The mesoderm is one of the three embryologic histological classifications – namely endoderm, mesoderm, and ectoderm. The cells of the endoderm morph primarily into the internal organs. The cells of the mesoderm level develop into dermis and hypodermis, fatty tissues, and the musculoskeletal system, and the ectoderm becomes, among other tissues, the brain and epidermis. The term mesotherapy therefore is in reference to injecting into those tissues that originate from the mesoderm, namely the dermis and hypodermis. It is important to understand that the mesoderm exists only in embryos. Contrary to a current, common erroneous statement made by English language mesotherapists, there is no mesoderm layer of the human skin. One is not "injecting into the mesoderm," rather one is injecting into those structures that have arisen from mesoderm.

The proposed mechanism of action of mesotherapy is that solutions injected intracutaneously remain in the area longer than they would by deeper injection because they are slower to be cleared by general circulation. Further, it is felt that these solutions injected superficially continually penetrate into the deeper tissues.

Kaplan and Raincourt injected radioisotope-marked calcitonin and found, upon serial scans, that the more superficial the injections, the longer the solution remained in the area.⁸ LeCoz and DuPont conducted an experiment on patients scheduled to undergo arthroscopic surgery of the knee. The subjects were divided into three groups. The first group received intra-epidermic papules of a diluted non-steroidal anti-inflammatory drug (NSAID), the second group received sub-cutaneous injections of the same solution using 4 mm needles, and the third received deep intramuscular injections of the same solution. At hours one and three post-injection, venous blood draws were performed to determine serum levels of the NSAID. It was found that, uniformly, the more shallow the injection, the lower the level of the substance present in venous circulation at both one-hour and three-hours post-injection. During arthroscopy, synovial biopsies were performed, and all groups were found to have NSAID present, although tissue concentration levels were not determined.⁹ Mesotherapy therefore appears to be a novel technique to administer medicines local to the pathology while the skin acts as a natural time-release system.

Injection Techniques
Three principle mesotherapy injecting techniques currently exist: namely, point by point, nappage (French for "covering"), and epidermic:

Point by point was first described in the context of mesotherapy by Dr. Pistor. It is very simply the injection of 0.02cc to 0.05cc of solution after perpendicularly inserting a 4 mm, 6 mm, or 12 mm needle its entire depth. Point by point injections are generally given 1-2 cm apart and sparingly.

Nappage, first described by Bourguignon and Ravily,¹⁰ is a more superficial technique that takes practice to master. With the syringe held at a 45-degree angle from the skin and while applying light, constant positive pressure on the syringe's plunger, the practitioner rapidly flicks the wrist in a way that can mimic the shaking of a salt shaker or the action of a sewing machine while covering a large area of skin. Generally, a 4 mm needle is used and is not fully inserted, only 0.5-2 mm deep, and only a drop of solution is introduced at each site at approximately 0.25 cm-0.5 cm intervals. In this way, one is able to infuse a large area of skin with the solution while achieving a profound cutanous stimulation that mimics certain ancient acupuncture practices. When performed correctly, one will perform a "sweep" of nappage, and pinpoint bleeding will occur five to ten seconds later. Nappage is, without a doubt,the least comfortable technique for the patient.

Epidermic, first described by Perrin,¹¹ is the most superficial of the techniques. When performed correctly, the basal layer is not penetrated. Dr. Perrin developed this technique in 1989 in order to be able to perform mesotherapy on children without pain. A 13 mm (or half-inch) 27-31 gauge needle is positioned at a very steep angle to the surface of the skin. Then, with the bevel oriented away from the skin, it is dragged along the skin while light positive pressure is applied to the syringe's plunger. The needle will bend slightly from the angle and the pressure. When treating certain anatomical contours such as the cervical spine and the occipital ridge, the practitioner may bend the needle before treating in order to maintain a correct needle position. Most practitioners will use a slight bouncing action described as "Parkinsonian."

Epidermic technique is intended to produce a shallow groove in the uppermost layers of keratinized epithelial cells ,which in turn is covered with a bead of solution. When performed correctly, there is no bleeding or scratching, but one is able to see the solution quickly absorb into the skin. Epidermic technique is done in a grid pattern at 1 cm intervals over the entire affected area. When either nappage or epidermic technique are performed, the patient must be advised to avoid "spray-on tanning" for a minimum of 24 hours post-treatment to avoid a visually bizarre result.

Mesotherapy for the Treatment of Pain
While the clinical applications of mesotherapy outside the realm of non-surgical cosmetic medicine are almost entirely unheard of in the US, in France, the birthplace of mesotherapy, mesotherapy is first and foremost a pain and sports medicine modality. Mesotherapy is of particular interest to clinicians due to its safety, tolerability to patients, cost-effectiveness, and seeming efficacy when compared to conventional treatment protocols. This discussion is meant to give an overview of mesotherapy as it is practiced in France for the treatment of chronic pain and acute injury.

Local anesthetics are used in the vast majority of mesotherapy protocols. Either lidocaine 1% or procaine 1%, always without epinephrine is used. Local anesthetics are used for their anesthetic properties that are believed to be longer-acting when injected mesotherapeutically. As is taught by the French Society of Mesotherapy, lidocaine is generally indicated for treatment of acute conditions, while procaine is indicated for chronic conditions because of its additional vasodilatory properties.¹²

In France, mesotherapists commonly use the vasodilatory medication buflomedil (Fonzylane) when treating pain. Buflomedil is not available in the US. Pentoxifylline (Trental), also commonly used in France, is an FDA-approved medication that is not a true vasodilator but may be used in place of buflomedil in the US.

Pentoxifylline's on-label use is for the treatment of intermittent claudication, and it improves microcirculation by decreasing the blood's viscosity and by improving erythrocyte flexibility. Pentoxifylline has been shown to increase leukocyte deformability and inhibit neutrophil adhesion and activation. Tissue oxygen levels have been shown to significantly increase with therapeutic doses of pentoxifylline in patients with peripheral arterial disease.¹³

Mesotherapists believe that, by increasing microcirculation of localized tissue beds, the elimination of metabolic waste is facilitated, and there is an increase in the delivery of the mesotherapeutic solution and oxygen. By injecting pentoxifylline mesotherapeutically, it is believed to exercise its therapeutic effect for a longer period of time compared to other routes of administration.¹⁴

Pentoxifylline has been shown in animal studies to exert antinociceptive activities. It is a tumor necrosis factor-alpha and interleukin-1-beta antagonist,¹⁵ and it has been shown to be an interleukin-1-alpha receptor agonist, which thereby limits inflammatory hyperalgesia.¹⁶ Local administration of pentoxifylline causes inhibition of proinflammatory cytokine synthesis and antagonizes hyperalgesia in formalin-injected rats.¹⁷

Of particular interest is French mesotherapists' liberal use of salmon calcitonin (sCT) for the treatment of a broad spectrum of chronic pain disorders. sCT is best known as an anti-osteoporotic agent administered as a nasal spray, but its analgesic effects in the treatment of acute osteoporotic fracture has been well-documented.^18-21 Researchers have examined the anti-nocioceptive properties of sCT for a range of disorders including advanced metastasic malignancy,^22-24 reflex sympathetic dystrophy,²⁵ phantom limb pain,^26-28 and diffuse sclerosing osteomyelitis of the humerus.²⁹ One animal study demonstrated sCT's ability to increase the analgesic effect of amitriptyline and paroxetine.³⁰

The mechanisms of analgesic action of sCT are believed to be multifactorial. An anti-inflammatory action has been suggested.³¹ Studies in animals and in humans demonstrate that in some, but not all, cases, calcitonin increases plasma beta-endorphin levels.³² It is possible that specific binding sites for salmon calcitonin exist in the brain.³³

It merits mention that while the clinical use of sCT appears safe, it is not without risk of side effect or adverse reaction. Nausea without vomiting and mild local inflammatory reactions at the site of injection occurs in approximately ten percent of patients receiving sCT, and transient severe nausea and vomiting occurs in approximately one in 300 patients. Flushing of face or hands, skin rashes, nocturia, pruritus of the ear lobes, feverish sensation, pain in the eyes, poor appetite, abdominal pain, edema of feet, and salty taste have been reported. Administration of sCT has been reported in isolated cases to cause hypersensitivity reactions.³⁴

The majority of scientific data in the field of mesotherapy in the treatment of pain and sports medicine currently are in the French language and consist of clinical case series. These papers are published in the journal of the French Society of Mesotherapy, which is not MedLine-indexed but has been in continual print for 30 years. One such clinical case series showed mesotherapy to be beneficial in the treatment of 65 patients suffering from chronic thoracic back pain from arthritis, spinal stenosis, and sprain/strain not adequately controlled with conventional methods – namely, NSAIDs, narcotic analgesics, muscle relaxants, and physiotherapy.³⁵ Another clinician describes his results of having treated 267 cases of degenerative arthritic pain and suggests that mesotherapy appears to be an effective and reasonable treatment option, especially in light of the complete absence of adverse side effects or reactions in the treatment group.³⁶ One paper describes the mesotherapeutic treatment of 210 patients with various soft tissue musculoskeletal pain not satisfactorily controlled with conventional methods. These patients were treated mesotherapeutically with local anesthetics, NSAIDs, sCT, and a non-sedating centrally acting muscle relaxant (thiocolchicoside), and the results suggest mesotherapy to be a reasonably effective treatment option, especially in light of poor patient toleration to injection of corticosteroids.³⁷ Another paper that describes the use of mesotherapy on 132 cases of patients with back and neck pain not ameliorated after three months of conventional treatment also shows mesotherapy to be a promising treatment option in terms of safety and efficacy.³⁸ Mesotherapy has been shown to be helpful in a variety of commonly seen sports medicine conditions, such as Achilles tendonitis.³⁹ Lambert describes his success in treating 48 cases of Osgood Schlatters.⁴⁰

A systematic review and descriptive analysis of the current data and better-constructed large scale trails are needed. However, mesotherapy appears to be a promising modality in the treatment of a spectrum of painful disorders. It is of particular interest to clinicians because of its excellent safety profile, tolerability to the patient, cost-effectiveness, and seeming efficacy.

In France, a spectrum of condition-specific protocols exists, however, I encourage those learning mesotherapy for the treatment of pain to use the following treatment solution. I have presented this formula to the entire board of directors of the French Society of Mesotherapy, and they have agreed that this protocol may be considered appropriate for both acute injury and chronic pain. I teach this protocol as it consists of ingredients that are at the same time safe, effective, and readily available internationally:

50IU salmon calcitonin
1cc Pentoxifylline 20mg/mL
1cc lidocaine 2%
0.5cc multivitamin (optional – available as a "meso-multi" from a number of US compounding pharmacies)

Those interested should view "Mesotherapy Instructional Text and DVD" to see condition-specific injecting techniques. For more information, please visit http://www.mesotherapyworldwide.com/Adelson_Training.htm.

Notes
1. LeCoz J. Mésothérapie en Médecine Générale. Ed Masson: 1993.
2. Ibid.
3. Ibid.
4. Laurens D. [Suivi traumatologique des perchistes de l'INSEP de juillet 1998 a juillet 2000.] Presented at the 9th" International Mesotherapy meeting of the French Society of Mesotherapy, Paris, October 20-22, 2000. Conference manual. 2000;145-162.
5. Roch FX. [Place de la Mesotherapie dans un centre anit-douleur.] Presented at the 9th International Mesotherapy meeting of the French Society of Mesotherapy, Paris, October 20-22, 2000. Conference manual. 2000; 53-63
6. Belhocine M. Oussedik E. [Dix annees de mesotherapie en traumatologie du sport au C.N.M.S.] Presented at the 9th International Mesotherapy conference of the French Society of Mesotherapy, Paris, October 20-22, 2000. Conference manual. 2000;199-206
7. LeCoz, op cit.
8. Kaplan A, Raincour. [Devernir d'un produit marque injecte par quatre voies differentes.] Bulletin SFM. 1985: 62.
9. LeCoz J, Dupont J-Y. [L'injection en regard du genou par voie mesotherapique donne de bonnes concentrations intra-articularires.] Quotidien du Medecin. September 20, 1983.
10. Mrejen D, Perrin JJ. Mesotherapie et Rachis. Editions S.F.M. CERM Ile de France, CRM Champagne, 2003.
11. Ibid.
12. La Pharmacopee en Mesotherapie. 3rd edition. Societe Francaise de Mesotherapie, 2001.
13. Mosby's Drug Consult. St. Louis, Missouri: Mosby, Inc., an Elsevier Science Company.
14. LeCoz, op cit.
15. Vale ML, et al. Antihyperalgesic effect of pentoxifylline on experimental inflammatory pain. Br J Pharmacol. 2004 Dec;143(7):833-44. Epub 2004 November 1.
16. Cunha JM. Cytokine-mediated inflammatory hyperalgesia limited by interleukin-1 receptor antagonist. Br J Pharmacol. 2000 Jul;130(6):1418-24.
17. Dorazil-Dudzik M, et al. The effects of local pentoxifylline and propentofylline treatment on formalin-induced pain and tumor necrosis factor-alpha messenger RNA levels in the inflamed tissue of the rat paw. Anesth Analg. 2004 Jun;98(6):1566-73.
18. Gennari C. Analgesic effect of calcitonin in osteoporosis. Bone. 2002 May;30(5 Suppl):67S-70S.
19. Silverman SL, Azria M. The analgesic role of calcitonin following osteoporotic fracture. Osteoporos Int. 2002 Nov;13(11):858-67.
20. Lyritis GP, Ioannidis GV, Karachalios T, Roidis N, Kataxaki E, Papaioannou N, Kaloudis J, Galanos A. Analgesic effect of salmon calcitonin suppositories in patients with acute pain due to recent osteoporotic vertebral crush fractures: a prospective double-blind, randomized, placebo-controlled clinical study. Clin J Pain. 1999 Dec;15(4):284-9.
21. Mehta NM, Malootian A, Gilligan JP. Calcitonin for osteoporosis and bone pain. Curr Pharm Des. 2003;9(32):2659-76.
22. Allan E. Calcitonin in the treatment of intractable pain from advanced malignancy. Pharmatherapeutica. 1983;3(7):482-6.
23. Mystakidou K, Befon S, Hondros K, Kouskouni E, Vlahos L. Continuous subcutaneous administration of high-dose salmon calcitonin in bone metastasis: pain control and beta-endorphin plasma levels. J Pain Symptom Manage. 1999 Nov;18(5):323-30.
24. Szanto J, Jozsef S, Rado J, Juhos E, Hindy I, Eckhardt S. Pain killing with calcitonin in patients with malignant tumours. Oncology. 1986;43(2):69-72.
25. Appelboom T. Calcitonin in reflex sympathetic dystrophy syndrome and other painful conditions. Bone. 2002 May;30(5 Suppl):84S-86S.
26. Wall GC, Heyneman CA. Calcitonin in phantom limb pain. Ann Pharmacother. 1999 Apr;33(4):499-501.
27. Simanski C, Lempa M, Koch G, Tiling T, Neugebauer E. [Therapy of phantom pain with salmon calcitonin and effect on postoperative patient satisfaction.] Chirurg. 1999 Jun;70(6):674-81.
28. Jaeger H, Maier C. Calcitonin in phantom limb pain: a double-blind study. Pain. 1992; 48:21–27.
29. Donnelly S, Doyle DV. Chronic diffuse sclerosing osteomyelitis of the humerus: novel treatment with calcitonin. J Rheumatol. 1993 Jun;20(6):1073-6.
30. Ormazabal MJ, Goicoechea C, Sanchez E, Martin MI. Salmon calcitonin potentiates the analgesia induced by antidepressants. Pharmacol Biochem Behav. 2001 Jan;68(1):125-33.
31. Azria M. Possible mechanisms of the analgesic action of calcitonin. Bone. 2002 May;30(5 Suppl):80S-83S.
32. Franceschini R, Cataldi A, Cianciosi P, Garibaldi A, Corsini G, Barreca T, Rolandi E. Calcitonin and beta-endorphin secretion. Biomed Pharmacother. 1993;47(8):305-9.
33. Lyritis GP, Trovas G. Analgesic effects of calcitonin. Bone. 2002 May;30(5 Suppl):71S-74S.
34. Mosby's Drug Consult, op cit.
35. Smail H. [Douleurs thoraciques anterieures d'origine vertebrale.] Presented at 9th International Mesotherapy conference held by the French Society of Mesotherapy, Paris, October 20-22, 2000.
36. Leah da Silva J, Mesquita ME. [Resultants de l'evaluation de deux annees de traitemment de la douleur par mesotherapie dans les rhumatismes degeneratifs chroniques.] Presented at 9th International Mesotherapy conference held by the French Society of Mesotherapy, Paris, October 20-22, 2000.
37. Chos D. [Enquete retrospective des tendino-myalgies du rachis rencontrees dans une consultation de rhumatologue dans le cadre d'n centre anti douleur.] Presented at 9th International Mesotherapy conference held by the French Society of Mesotherapy, Paris, October 20-22, 2000.
38. Messedi-Kamoun N, Ben Salah FZ, Dziri C. [La Mesotherapie dans les douleurs rachidiennes experience Tunisienne a propos de 132 cas.] Presented to 9th international mesotherapy conference held by the French Society of Mesotherapy, Paris, October 20-22, 2000.
39. Bourit G, Guerin P. [Propositions therapeutiques dans la pathologie du tendon calcaneen. Presented in 9th International Mesotherapy conference held by the French Society of Mesotherapy, Paris, October 20-22, 2000.
40. Lambert Y. [Place de las mesotherapie dans le concert therapeutique de la douleur chronique.] Lave Revue de Mesotherapie. 2000;1.