pharmacological sciences 2011; 15: 682-694 … management of chronic venous lymphatic in- ......

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Abstract. – Objective: Since its introduc-tion in the 1950s, the use of mesotherapy hasgenerated much interest among clinicians andpatients. The Italian Society of Mesotherapy(SIM) brought together a panel of experts to re-view available evidence and to draw up a seriesof recommendations on the use of intradermaltherapy (LIT) in clinical practice.

Consensus Report: There was overwhelmingagreement among Consensus Group membersthat, when used correctly, LIT is a valuable thera-peutic option in the treatment of painful, loco-re-gional conditions. They also emphasised that theclinical efficacy of LIT has been demonstrated inthe management of chronic venous lymphatic in-sufficiency, oedematous fibrosclerotic pannicu-lopathy and facial skin aging. The experts wereunanimous on the use of LIT in vaccination.Mesotherapy is not a substitute for other therapeu-tic options and should only be used when the pa-tient has been fully informed of its advantages andlimitations. Likewise the procedure should only becarried out by an experienced qualified physician.

Conclusions: Although there was widespreadagreement among the Consensus Group on theplace of LIT in several indications, the Authorsreiterated the need for more large-scale clinicaltrials to determine the specific benefits and limi-tations in some areas of the application of intra-dermal therapy.

Key Words:

Mesotherapy, Intradermal therapy, Consensus Report.

Introduction

Pharmacological products have been given in-tradermally for over a century1-6, but it was notuntil much later that this method became more

European Review for Medical and Pharmacological Sciences

Corresponding Author: Massimo Mammucari, MD, President of Italian Society of Mesotherapy;e-mail: [email protected]

widely accepted. A French physician, MichelPistor7, reported encouraging results with smalldoses of drugs administered intradermically topatients with a variety of clinical conditions. Theterm “mesotherapy” comes from the Greek word“mesos” – referring to the mesoderm (or middlegerm cell layer) in the early embryo which dif-ferentiates into tissues and structures, includingbone, cartilage, muscle and connective tissue.

Initially, mesotherapy consisted of the use of amixture of active ingredients combined with pro-caine in the same syringe8-10. These “cocktails”of agents showed many beneficial effects, al-though systematic well-conducted preclini-cal/clinical studies were lacking. Furthermore, notrials were conducted to determine the safe-ty/toxicity or pharmacological (pharmacokinet-ic/pharmacodynamic) interactions of these mix-tures in humans.

The Italian Society of Mesotherapy (SIM) wasconceived in 1975 with the primary objective ofevaluating and validating mesotherapy in Italy us-ing scientific methods. In some of the first trialsthe pharmacokinetics and tolerability of a singlepharmaceutical agent administered intradermallywere investigated and since then the first treat-ment protocols were applied. At the outset theSIM took an important decision – to use a singleactive ingredient instead of a mixture of productsin the same syringe – in this way the efficacy andtolerability of individual agents could be closelymonitored. Recently, we brought together a Panelof Experts from a range of specialities to reviewand validate the scientific rationale, advantages,indications and contraindications on the use ofmesotherapy, with the aim of formulating a seriesof recommendations on the appropriate use of lo-cal intradermal therapy (LIT).

2011; 15: 682-694

Mesotherapy, definition, rationale andclinical role: a consensus report fromthe Italian Society of Mesotherapy

M. MAMMUCARI1, A. GATTI1, S. MAGGIORI2, C.A. BARTOLETTI2, A.F. SABATO1

1Emergency Care, Critical Care Medicine, Pain Medicine and Anesthesiology Department, Tor VergataPolyclinic, University of Tor Vergata, Rome (Italy)

2SAMEST, International Foundation Fatebenefratelli, Rome (Italy)

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Mesotherapy in Italy: a consensus

This review describes current views on the useof LIT from the perspective of the SIM. Guide-line statements and recommendations were se-lected and voted on using formalised consensusprocedures.

Definition of Mesotherapy by SIMMesotherapy is a minimally invasive technique

that consists of LIT with pharmaceuticals or oth-er bioactive substances given in small quantitiesthrough dermal multi-punctures, where the injec-tion site corresponds to the area of the pathologi-cal condition11. LIT is used when no other thera-py options exists; when other therapies havefailed (or for whatever reason cannot be used);when there is a possible synergistic benefit withother pharmacological/non-pharmacologicaltherapies, and importantly when LIT can have asystemic drug-sparing role.

Pharmacological and clinical experience is re-quired for the correct application of mesotherapyand disregard for the correct medical proceduresconstitutes medical malpractice. Used correctly,mesotherapy is effective in the treatment ofpainful musculoskeletal conditions, chronic ve-nous lymphatic insufficiency (CVLI), oedema-tous fibrosclerotic panniculopathy (OFP, morecommonly known as cellulite), intradermal vac-cination, and in the management of facial skinaging. It should be emphasised that mesotherapyshould only be used when the patient has beenfully informed of its advantages, limitations andpossible risks.

Rationale, Pharmacology andBasic Research

Mesotherapy is based on the principle that LITproduces a “micro deposit” of the drug in thedermis which is then slowly released into the sur-

rounding tissues. In other words, LIT allows ef-fective concentrations of products to reach thetarget area and (in theory) allows lower doses tobe administered compared with p.o./i.m. routes.The concept of the slow release of substance fol-lowing LIT has already been confirmed in pre-clinical trials12-15. With LIT the “first pass effect”is avoided and, therefore, using a prodrug is notappropriate. While it is well known that cy-tochrome P450-dependent enzymes in the liverplay an important role in metabolism of manysubstrates, the role of the cutaneous cytochromeenzyme system is less well understood16-18. It isthought to play an important, but as yet not com-pletely understood, role when a substance is ad-ministered transcutaneously or intradermally.One of the main advantages of LIT is the rapidrate of onset, due to the short time necessary toreach the site of action, as well as a prolonged lo-cal action. This method does not alter the mecha-nism of action of a given drug, which remainsunchanged irrespective of the administration site.However, it is clear that, for example, intrader-mal administration of a loop diuretic to the skinof the lower body with the aim of reducing oede-ma does not make pharmacological or clinicalsense.

In order to accept the concept of mesotherapyit is necessary to demonstrate that a drug admin-istered intradermally remains in the surroundingtissue for longer than the same drug administeredi.m. In the first series of pre-clinical studies thepharmacokinetics of drugs administered intrader-mally and i.m. were compared. A group of re-searchers19 demonstrated that higher concentra-tions of procaine chloride reach the underliningtissues (muscles and joints) following intrader-mal compared with i.m. administration (Table I).Furthermore, intra-articular levels of the drug

Skin Muscle Articular tissue

Time after i.m. (hours) LIT i.m. LIT i.m. LIT i.m.

0.5 27.40 ND 2.60 ND 0.30 ND1.0 9.60 ND 1.80 ND 1.15 ND2.0 2.80 ND 0.80 ND 0.65 ND4.0 0.80 ND 0.70 ND 0.10 ND7.0 0.50 ND 0.20 ND 0.05 ND

10.0 0.20 ND 0.02 ND 0.01 ND

Table I. Tissue levels of procaine (µg) following LIT or i.m. administration. Modified with permission from (19).

ND – not detectable.

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M. Mammucari, A. Gatti, S. Maggiori, C.A. Bartoletti, A.F. Sabato

ple injections. In general 0.10-0.20 mL of prod-uct is used and injection points are usually 2 or 3cm apart. Where large areas of skin need to betreated, the drug may be diluted but this reducesthe dosage and, therefore, additional or more fre-quent injections are necessary. However, the in-creased number of injections may not be advan-tageous for the patient. As a result, the SIM rec-ommends using a standard protocol with slightmodifications to reduce injection site effects(pain and bruising). It is important that the nee-dle is inserted quickly, but gently, and that the sy-ringe is emptied slowly. Clearly, the treatmentprotocol (choice of drug, duration of treatment,patient management and follow-up) varies de-pending on the nature, severity and site of thecondition being treated as well as pharmacologi-cal and clinical parameters11. In some cases thepH of LIT can cause severe pain but regulatingthe pH with sodium bicarbonate can reduce thiseffect23.

We do not recommend the use of a mixture ofdrugs in the same syringe because this proce-dure is not without risks. There are no in vitro/in vivo data on possible drug interactions, al-though changes in pH, colour and precipita-tion/flocculation have been observed when mix-tures of drugs are used. Moreover, when usingdrug mixtures it is not possible to identify the ex-act effects of individual drugs both in terms ofefficacy and tolerability. The risk of allergic reac-tions preclude the intradermal administration of amuscle relaxant plus a non-steroidal anti-inflam-matory agent (NSAID) in the same syringe – as

were detectable after LIT only and not with i.m.administration (Tables II-III). Likewise, tissuelevels of sodium-ketoprofen were detectable for alonger time post-LIT compared with post-i.m.administration (Figure 1)20.

Based on these results it has been suggestedthat LIT allows the total drug dosage necessaryto treat a given loco-regional condition to be re-duced. In pre clinical it has also been demon-strated that the anti-tetanus vaccine injected in-tradermally produces a greater immune response(both primary and secondary) compared with thesame antigen administered i.m.21, reinforcing thedrug sparing effects of LIT. It has been referredthat mesotherapy has a dual mechanism of action– in addition to the local effect of the drug – theprocess of introducing needles into the skin stim-ulates a reflex action thereby increasing endor-phin levels22.

The observations that intradermal administra-tion results in micro drug deposits that allow aslow and progressive diffusion of the drug intothe surrounding tissues and that LIT has addi-tional benefits on peripheral sensitivity, led manyworkers to study the use of LIT in a range ofconditions including the musculoskeletal disor-ders. Initial clinical trials investigated the effectsof a number of active ingredients to determinethe optimal dosage and frequency of administra-tion (plasma half-life of drugs administered intra-dermally does not necessarily correspond withthe duration of the loco-regional effects).

Materials and Methods for Performing LITMesotherapy is characterized by its unique

method of injection – active ingredient is injectedsuperficially using special short needles, directlyover the site of the underlying structures affected.Practitioners usually use 4 mm (27 gauge) or 13mm (30 or 32 gauge) needles where the needle ispositioned at a steep angle. The SIM recom-mends the use of a single needle instead of multi-

Time (hours) LIT i.m.

0 100 1000.5 74.8 1.61.0 41.9 ND2.0 32.2 ND

Table II. Tissue levels of procaine (%) after LIT and i.m.administration. Modified with permission from (19).

ND – not detectable.

Figure 1. Skin dermal, muscle and articular tissues levels(%) following i.m and intradermal administration of keto-profen sodium. Modified from (20).

LIT i.m.

%

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it is not possible to determine which drug hascaused the allergy. However, in a recent study itwas shown that NSAIDs can be used safely incombination with other active agents24.

A number of devices (mechanical and elec-tronic) are now readily available for LIT. Themanufacturers of these devices claim that somedevices allow rapid and painless injection whileothers deliver drugs to the skin without the needfor needles. None of the currently available de-vices is recommended by the SIM. At present,only the “physician’s hand” guarantees “true” in-tradermal administration.

Role of LIT in Acute and Chronic PainPain, an unpleasant sensory and emotional ex-

perience, acts as a natural alarm associated withactual or potential tissue damage; if pain persistsit can become a syndrome/condition in its ownright25,26. Nociceptive pain is caused by stimula-tion of peripheral nerve fibers that respond tostimuli approaching or exceeding harmful inten-sity (nociceptors). When pain persists the sensi-tive feedback system is altered and the microgliacells are activated25,27. The glia release neuro-transmitters which in turn activate the nocicep-tive defence system25. It is, therefore, importantthat pain therapy is started quickly and in a sys-tematic manner to prevent it becoming chronic.The dual mechanism of action of LIT – pharma-cological and local stimulation – has a rationalescientific basis as part of a therapeutic strategyfor localised pain control. In 1975 the SIM insti-gated a series of multicentre studies with the aimof testing the effect of LIT in patients with os-teoarticular pain (arthritis of the hip/knee/hand,neck pain, lower back pain, tendinopathy)28-33.The results of these studies confirm the efficacyand tolerability of anti-inflammatory/analgesicadministered as LIT (Table III).

Several Authors have reported encouraging re-sults with LIT in combination with physical thera-py34,35, in sports injuries36, in the management ofneuropathic pain37, as adjuvant therapy in thetreatment of osteoporosis pain38 and calcified ten-dinitis of the shoulder39-41. Others have used thetechnique for the treatment of musculoskeletalpain42-49. The use of anti-inflammatory/analgesicdrugs intradermally in osteomuscular conditionsappears to be one of the best and important indica-tions for mesotherapy. The drug-sparing effect ofthis procedure, when combined with other sys-temic therapies, should be quantified to measurealso advantages in cost effectiveness.

The role of LIT in Veno-Lymphatic EdemaCertain drugs when administrated intradermal-

ly exhibit a local trophic action. This effect wasfirst noted clinically when the healing of decubi-tus ulcers was improved following mesotherapyin spinal patients50. Likewise LIT improved sub-jective and objective symptoms (venous pressureand calf circumference) in patients with veno-lymphatic insufficiency51,52.

LIT has also be reported to improve OFP53.The exact cause of OFP is the subject of muchdebate but it is thought changes in the microcir-culation and chronic oedema (as a result of struc-tural changes in the adipose cells and the forma-tion of micronodules) are important predisposingfactors54,55. Active substances that affect the mi-crocirculation administered intradermally may,therefore, produce clinical improvements (bothsubjective and objective) in patients with CVLIand those with OFP56. Subcutaneous echographyhas made it possible to investigate microcircula-tory changes following LIT and to establish bet-ter inclusion/exclusion criteria to improve therisk/benefit ratio57,58.

Number of Outcome Pain disease (reference) patients (%)

Osteoarticular pain (28) 492 79.9Osteoarticular pain, acute myositis, tendino-muscular pain syndrome (29) 484 83.6Osteoarticular pain, tendinitis, epicondylitis (30) 193 91.0Osteoarticular pain (31) 46 78.0Osteoarticular pain (32) 256 52.7

(54.7 improvementin articular function)

Pain from gonarthrosis (33) 20 90.0

Table III. Initial studies with clinical benefits in pain diseases.

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LIT in Skin Aging Skin aging is in part genetically-determined

and in part the result of lifestyle and environ-ment. There are essentially two types – intrinsicor chronological aging and extrinsic or photoag-ing. In chronological aging the protective func-tion of the skin barrier is impaired; the produc-tion of sebum and perspiration are reduced; im-mune function is decreased and pigmentation,keratinisation and temperature regulation are al-tered. These factors taken in concert reduce thestructural function of the epidermis and dermis.

Photoaging describes damage to the skin causedby intense and chronic exposure to sunlight. Thevisible effects of photoaging are fine wrinkles,mottling and pigmentation and skin roughness. Cu-taneous biostimulation is the process of injectinginto the skin medical devices (approved in Italywith directive 93\42\CEE June, 14th 1993) ordrugs to improve skin elasticity/appearance and toreduce the signs of chronological and photoaging.The use LIT in skin rejuvenation (in particular forfacial skin) is now widely used and improvementscan be monitored using echographic techniques58.

During skin aging there is a loss of subcuta-neous fat, structural remodelling of cartilage andbone, and the formation of fine/expression linesfrom repetitive muscle activity. Hypertrophy ofthe subcutaneous tissue and the pull of gravitymean that excess skin forms into folds, lines andwrinkles – which can be treated by the adminis-tration of completely absorbable fillers59,60.

LIT – Local Lipolytic EffectsLikewise in the management of local adiposity,

LIT has demonstrated encouraging clinical re-sults61-66 but there are still doubts regarding the trueefficacy and safety of the products administered. Inmany papers Authors do not distinguish betweenLIT, subcutaneous and deep intralesional adminis-tration and there is a tendency to group these threetypes of administrations under one single entity:mesotherapy67. This is one of the reasons why LITin cosmetic medicine is not without its critics67-69.Controlled large scale clinical trials, conducted inaccordance with Good Clinical Practice (GCP) are,therefore, urgently required to determine the safetyand lipolytic effects of pharmaceutical active prod-ucts administered as LIT.

This is the reason why a long time ago the Ital-ian Society of Mesotherapy decided to exclude thisindication from clinical protocols. Recently alsothe Minister of Health in France decided to prohib-it cocktails administered by mesotherapy in this


clinical condition (decree n 382-2011). RCT in thisarea are needed to clarify this issue.

Role of LIT in Dermatological Conditions Many skin lesions can potentially benefit from

local injections, and early reports have describedgood results with a corticosteroid, in patients withcystic acne, alopecia and keloids70. However, thisclass of drugs should be used with special care be-cause of multiple effects on the skin. The LITplays an important role when in reducing the sys-temic dose of drugs and consequently adverseevents71. However, many treatments describe anintralesional injection (as in cystic acne or keloids)not intradermally (as in the case of alopecia).

Role of LIT in VaccinationAmong the first reported uses in the literature

of LIT were in vaccination1,2. The dermis has amicrocirculation which can interact with the im-mune system and intradermal inoculation of vac-cines provides a number of advantages over i.m.administration – including a reduction in the anti-gen dose required, reduced need for adjuvant, agreater immune-response and a simpler mode ofadministration21,72,73. The efficacy of LIT providesthe stimulus to research new devices/methods sothat (for example) mass vaccinations can be car-ried out in a simpler manner.

Role of LIT in Pediatric PatientsThe use of LIT in children has also been inves-

tigated in studies conducted in Italy. Followinginitial preclinical trials with ACTH and pred-nisolone administered intradermally, efforts weremade to reduce the stress caused with p.o. admin-istration by employing the intradermal route74,75.Preliminary data with intradermal prednisolone inbabies with asthma have shown encouraging re-sults with a dose of prednisolone 3-10 times lowerthan that required with p.o. therapy and with theadded benefit that it is not necessary to graduallyreduce the dosage76. More controlled large trials inthis patient group are required.

Role of LIT in Otolaryngology (ENT)LIT has also been used in some otolaryngolo-

gy or ENT (ear, nose, and throat) conditions toreduce the systemic dosage of drugs and relatedside effects. In fact, interesting results have beenreported in patients with tinnitus, both versusplacebo77 and active oral therapy78. Reduction ofphlogosis and pain and no side effects were re-ported in auricular perichondritis of the external

auditory canal when low dosages of drugs wereadministered intradermally79. As with other clini-cal conditions, clinical and pharmacological ex-pertise is required to select patients for LIT orsystemic treatment.

Informed ConsentIn Italy the law states (judgment of the Court of

Turin 19/10/1985) that intradermal administrationshould be performed by a qualified medical doctoronly (and not by paramedics) and as with othermedical procedures, should be carried out withprudence, diligence and due skill. Obtaining in-formed consent from the patient is obligatory. Pa-tients should receive clear and complete informa-tion on the treatment proposed, based on the diag-nosis made, as well as information on the avail-ability of therapeutic alternatives. Before givingconsent, the patient should be fully aware of whatthe procedure involves. Importantly, if the doctorrecommends the off-label use of a drug or of atreatment the patients should fully understand therisks and benefits (written consent).

In order to improve the risk/benefit ratio theSIM has undergone a process to revise and sim-plify treatment protocols by reducing the numberof drugs in use and to discourage the use of acocktail of drugs in the same syringe. It shouldbe remembered that Italian law (Decree-Law No23, 1998) states that drugs can be administeredby a method different from their approved indi-cation – if there is no suitable approved alterna-tive or if there are international published paperssupporting off-label use (as also the code of med-ical ethics states in article 13).

Information on LIT should be given to the pa-tient in a clear and concise manner and the pa-tient should be told if the drug is approved for in-tradermal administration or not. Informed con-sent ensures that patients do not receive treat-ment with products whose efficacy and safetyhas not been fully established, as sometimes ithas been reported80. Physicians should includeobtaining informed consent in their diagnos-tic/therapeutic work-up (Figure 2).

Pros and Cons of LITLIT is the administration of low doses of a

drug directly at the site of the condition therebyreducing the need for systemic treatment of loco-regional conditions. Rare transitory and re-versible local and systemic adverse reactions (al-lergies, ecchymosis, urtica, granulomata) follow-ing mesotherapy have been reported11. However,

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in many published reports, details of treatmentare not given81-87. For example, the drug or mix-ture injected, the number of treatments, co-ad-ministration of systemic therapy, if therapy wasadministered by a qualified physician or not, andsite and depth of administration (if drug was ad-ministered into the dermal layer or deeper). Im-portantly, it is often not stated if standard hygieneprocedures were adhered to or if treatment wascarried out in a hospital setting by personneltrained in the management of drugs88.

Patients often ask their physicians for LIT foraesthetic reasons but they frequently underesti-mate the possible adverse events. This means thatphysicians need to carefully select patients and notto treat those who withhold important informationin order to get LIT. It is vital that the physicianoutlines the benefits and risks of therapy with ref-erence to published clinical experience so that pa-tient expectations are not unduly raised.

Physicians have a duty to report to the phar-macovigilance authorities any adverse eventsprobably/possibly related to a given drug or pro-cedure, including details of the treatment proto-col and concomitant medications.

Clinical Report FormAs in other areas of medicine, the importance

of accurately compiling a clinical report form

LITrequest bypatients

Diagnosticanalysis

Figure 2. Diagnostic/therapeutic work-up for intradermaltherapy (LIT) for patients who require it and when it repre-sents a therapeutic option.

Therapy options

Informedconsent

Informedconsent

Othertherapy

Intradermaltherapy

Periodic follow-up

Global assessment

Accurateclinical and

pharmacologicalhistory

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should not be underestimated for patients ongo-ing LIT. Patient files should record routine clini-cal characteristics as well as follow-up. The SIMrecommends the use of a specific clinical file torecord the protocol but also adverse events (seepart of the record as an example in Figure 3). TheSIM strongly recommends the need to report ac-curately the efficacy and tolerability of LIT foreach patient. Moreover, in Italy the medicalrecord, must also report the characteristics ofpain experienced, its evolution, as well as thedosage, mode of administration and type of anal-gesic drugs used as well as the pain controlachieved (Decree-Law No. 38, 2010).

Treatment AlgorithmLIT protocols allow for one or more cycles of

treatment depending on the symptoms and sever-ity of the underlying condition and the individualpatient’s response to therapy. For example whentreating a chronic painful condition there are nor-mally three distinct phases – attack – when four

weekly treatments are administered, a subsequentcontrol phase – four fortnightly treatments aregiven to confirm results and prevent short-termrecurrences and finally the maintenance phase –monthly or seasonal treatment. When treating re-sistant pain twice weekly therapy is recommend-ed in the “attack phase” depending on the anal-gesic effect obtained11. Likewise in patients withCVLI treatment can be more regular dependingon the clinical response and beneficial effects ob-served11. The task force of experts is now defin-ing specific protocols/algorithms to implementLIT in several conditions.

Consensus and RecommendationsTo validate the recommendations for the correct

use of LIT in Italy we used the Delphi Method – agroup decision making technique which seeks toachieve a Consensus among group membersthrough a series of questionnaires89,90. Web-basedquestionnaires were drawn up by the scientificcommittee and questions are answered anony-

Figure 3. Part of a medical record used to collect data during intradermal treatment.

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mously and individually by members of the Ex-pert Panel/Steering Committee (see Appendix).Answers were summarized and sent back to thegroup members together with the next question-naire. The process was repeated until a groupConsensus was reached. Recommendations with aConsensus >90% were classified as strong (S),those with a Consensus of 75-90% as good (G),those with a Consensus of 50-74% as weak (W)and those with a consensus <50% as rejected (R).The final approved recommendations are sum-marised in Table IV and Table V.

There was overwhelming Consensus amonggroup members that LIT is a valuable therapeuticoption in the treatment of painful, loco-regionalconditions. The experts also concluded that theclinical efficacy of LIT has been demonstrated inthe treatment of CVLI, OFP and skin aging. How-

ever, additional large-scale trials are required toconfirm the efficacy and tolerability of singleagents. The Panel were unanimous on the use ofLIT in vaccination. They emphasised that used cor-rectly by skilled practitioners, this technique repre-sents an important addition to the clinical arma-mentarium. LIT has not been tested and it is, there-fore, not recommended in the following patientgroups – patients with a history of allergic reac-tions, patients with disorders of coagulation(haemophiliacs, undergoing therapy with anticoag-ulants or anti-platelet agents), pregnant or lactatingwomen or cancer patients receiving chemotherapy.

Future Steps Mesotherapy is used with consent in many

countries around the world, although in some itsuse is under discussion because of the lack of

General recommendations Consensus

Mesotherapy is the intradermal administration of pharmacologically active ingredients directly over the Ssite of the underlying condition, structures, organs, or area affected; it is also known as local intradermaltherapy (LIT)

LIT should only be administered by a doctor with clinical and pharmacological experience SAdministration of LIT requires clinical and pharmacological experience so that contraindications to this Smethod of administration can be identified

LIT should only be used when there is a sound clinical rationale and after other therapeutic options have Sbeen considered

It is suggested that only established clinical protocols are used when the risk/benefits are known SThe use of previously untested compounds should be avoided (the exception being in clinical trials that conform to GCP)

The physician should supply the patient with all the necessary information on LIT in a clear and Sunderstandable manner so that he/she can make an informed decision

The patient’s clinical file should contain information on the LIT protocol (drug, dosage, frequency of Sadministration, condition to be treated) as well as details of the concomitant therapy (pharmacologicaland non-pharmacological)

All adverse events should be reported to the Pharmacovigilance Health Authorities SPhysicians administering LIT should undergo regular CME courses to keep up to date with clinical and Spharmacological developments

Methodological recommendations Consensus

The use of more than one drug in the same syringe increases the risk of pharmacological interactions – Sand therefore single-drug LIT is recommended at least until pharmacological and clinical largestudies demonstrate the efficacy and tolerability when one or more active ingredients are combinedin the same syringe

In some circumstances one or more active ingredients can be used (for example an anti-inflammatory and Sa muscle relaxant) but not in the same syringe and not at the same site of administration

LIT should only be administered in a medical environment using sterile single-use syringes and needles Saccording to accepted standard hygiene regulationsThe practice of using hospital-type containers from which the required amount of drug is taken is to be Savoided because of the risk of introducing microorganism into the container

Following use sharps and syringes should be disposed safely in the approved containers and care should Sbe taken not to contaminate sterile material

Table IV. Recommendations – general and methodological – from Consensus Panel.

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standards, or because it is used for cosmetic pur-poses by non-medical personnel67. However,there are still many unanswered questions. Scien-tific Societies have an important role to play indeveloping and supporting well-conducted clini-cal trials to address outstanding questions – in-cluding the dose-sparing effects of LIT in pa-tients receiving systemic treatment for chroniclocal pain, and the effects of LIT using differentpharmaceutical agents in patients with a range ofother conditions. In Italy retrospective studies toidentify more selective inclusion criteria for thetreatment with drugs57 and perspective trials areongoing to investigate the tolerability and the ef-ficacy of pharmacologically active compounds(data on file).

In general, well-conducted, large-scale trialsare required to define the specific benefits andlimits of a given therapy – only in this way pa-tients will be guaranteed to receive the most ap-propriate mesotherapy. Finally, misleading adver-tising on injectable products should also be mon-itored and discouraged91 and continuing medicaleducation (CME) for physicians by non-partisanorganizations should be mandatory to keep up-to-date and to avoid malpractice.

Conclusions

As with other therapies, mesotherapy (LIT)has advantages and disadvantages. The advan-

Specific recommendations for the use of LIT in localised pain Consensus

LIT is indicated for the control of some type of pain but should always be used as an integral part of Sa clinical management programme

Before using LIT pain should be classified based on the type and intensity of the pain preferably Susing a Numeric Scale (NRS 0-10 pain rating scale) or other validated scale

LIT represents a valid pharmacological option in the treatment of pain in particular osteo-muscular Sand articular pain

LIT can be used in combination with other therapies SUse of LIT is appropriate when there are no contraindications to the pharmacologically active agents SPatients should be clearly informed of the advantages and limitations of LIT S

Specific recommendations for the use of LIT in aesthetic medicine Consensus

LIT is a valid method to pharmacologically treat CVLI and its consequence OFP as well as in treatingfacial skin conditions (scars, aging) S

A clinical/psychological profile of the patients is recommended before beginning LIT SBefore starting LIT treatment the patients should be informed on the possible adverse events S(caused by needle injury and the process of injecting drugs locally)

For the use of LIT in esthetical facial skin aging, patients should be clearly informed of the realistic Sbenefits that the treatment can reach

LIT should only be used for esthetical reasons by physicians S

Clinical indications Consensus

Musculo-skeletal pain SMuscle contraction caused by osteoarticular, tendino-muscular pain syndrome SCVLI SCVLI with OFP SBiostimulation and esthetic effects on facial skin SIntradermal vaccination (with vaccines approved for this method of administration) SPatients under 18 years of age RPregnancy RLactation RImmunocompromised patients R

Table V. Specific recommendations – indications and contraindications for the use of LIT from the Consensus Panel.

CVLI - chronic venous lymphatic insufficiency, OFP oedematous fibrosclerotic panniculopathy.

tages are greater if LIT is carried out by medicalexperts. The disadvantages can be reduced if thephysician uses only agents that have undergoneclinically trials and are approved by the scientif-ic community. The lack of randomised con-trolled studies, published in the internationalscientific literature, does not invalidate the workof Michel Pistor† (Honorary President of theItalian Society of Mesotherapy), whom wethank for his contribution to the developmentand spread of mesotherapy. It is now up to clini-cal researchers to validate the advantages, limi-tations and further development of mesotherapy.It is important that National Health Authoritiesadequately consider the importance ofmesotherapy and its potential benefits in termsof effectiveness and drug sparing.

Appendix

Steering Committee of Italian Society ofMesotherapy (SIM): Maggiori Enrica (1), Barto-letti Emanuele (1), Giardini Manuela (1), Ja-covitti Silvia (1), Dario Dorato (1), Trocchi Glo-ria (1), Salciccia PierLuigi (1) Laurenza Massi-mo (2), Massironi Alberto (3) Mediati RoccoDomenico (4), Migliore Alberto (5), RocchiPiergiovanni (6), Vellucci Renato (4), FerranteMaurizio (7).

Expert Panel: Acinapura Rosa Antonietta (1),Antonaci Luciano (8), Bozzone Myriam (1), Ca-puto Maria Grazia (1), Carota Alessia (1), Cento-fanti Domenico (1), Cuguttu Anna (1), De IulioCinzia (3), Denni Alessia (1), Di Marzo Raffaele(9), Di Maggio Roberta (1), Domenico Romano(10), Feleppa Domenico (1), FontevecchiaMichele (1), Fraone Nadia (1), Giardini Manuela(1), Giorgio Chiara (11), Guglielmo Costanza(1), Loffredo Fiamma (1), Longo Giuseppe (12),Marchionne Antonella (1), Mariotti Mario (3),Nazzaro Letizia (1), Orlandi Clemente (3), Pom-pilio Alberto (1), Prosenikliev Vlatko (13),Redaelli Alessio (14), Santini Stefania (1),Savastano Marina (13), Tamburlin Nadia (3),Tomaselli Fulvio (1), Torquati Luca (15), TriulziMarina (3), Troili Fiammetta (1), Tunesi Lucio(3), Veraldi Maria (1), Zannella Carlo (1).

1) Service of Aesthetic Medicine “S. GiovanniCalibita” FBF Isola Tiberina Hospital, Rome,Italy

2) Dermatologist, Rome, Italy

691


3) Agorà, Società di Medicina ad Indirizzo Es-tetico, Milan, Italy

4) Palliative Care and Pain Therapy, CareggiUniversity Hospital, Florence, Italy

5) OU of Rheumatology “San Peter Hospital”Rome, Italy

6) Specialist in Forensic Medicine, EthicsCommittee of the Medical College, Bologna,Italy

7) Medical Director, S. Giovanni Calibita" FBFIsola tiberina Hospital, Rome, Italy

8) GP, ASL RME, Rome, Italy9) Sanofi Pasteur MSD, Scientific Department,

Rome, Italy10) Laboraf, San Raffaele Hospital IRCSS – Mi-

lan, Italy11) Rehabilitation Hospital Services, Altamura

(Bari), Italy12) Emergency Care, Critical Care Medicine,

Pain Medicine and Anaesthesiology Depart-ment, Tor Vergata Polyclinic, University ofTor Vergata, Rome, Italy School of aestheticMedicine, Agorà, Milan, Italy

13) Medical-Surgical Specialties Department,ENT Section, University of Padua, Italy

14) Vascular Surgery, Padua, Italy15) Dermatologist, Viterbo, Italy

––––––––––––––––––––Acknowledgements

The Authors would like to thank all experts for theirparticipation and support. The Authors thank ContentEd Net who provided editorial assistance and AnnaAmmendolia for the web-based consensus and techni-cal support (www.societadimesoterapia.it).

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