12° E.M.R.S.S.

COURSE
Program
Physical Agents - Up to Date
( THE STATE OF THE ART IN THE APPLICATION OF PHYSICAL MODALITIES)
Syracuse 07 – 10 November 2016

Use of drugs in Electrotherapy and

Evidence Based Medicine

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

What pops into your mind when I say
“electricity”?
Electric Eel ? Battery?
Lightning ?

OR PIKACHU?!

Benjamin Franklin? Charles Augustin de Coulomb? Alessandro Volta?

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

…And if I say “electrotherapy”?

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 What is the Electrotherapy?
• Electrotherapy is the use of electrical energy as a medical
treatment.
• In medicine, the term electrotherapy can apply to a variety
of treatments, including the use of electrical devices such
as deep brain stimulators for neurological disease.
• The term has also been applied specifically to the use of
electric current to speed wound healing.
• Additionally, the term "electrotherapy" or "electromagnetic
therapy" has also been applied to a range of alternative
medical devices and treatments.

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 History of electricity
19th -20th
2750 BC 600 BC
Century:
Ancient Egiptians Thales of
Miletus Modern
described electric
fishes Developments

In the 19th century it had

Middle Ages and the Renaissance become clear that electricity
Robert Boyle (1627–1691) and magnetism were related,
Experiments on the Origin of Electricity and their theories were
unified: wherever charges are
18th Century : basis for modern electrical technology
in motion electric current
Scientific understanding into the nature of electricity
results, and magnetism is due
grew throughout the eighteenth and nineteenth
to electric current
centuries through the work of researchers such as Volta,
Ampère, Coulomb, Faraday and Maxwell

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

When would you date the first
application of electricity in
medicine?

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

46 CE when Scribonius Largus, physician to
Roman Emperor Claudius, found that standing
on electric eels at the seashore could relieve
pain by causing numbness.

Late in the 18th century, Luigi Galvani, Italian physician

and philosopher, discovered that electricity could
stimulate muscle tissue when his charged metal scalpel
accidentally came into contact with the leg of a frog he
was dissecting in his laboratory, causing it to twitch.

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

19th Century, Guillaume Duchanne
• If a muscle did not
contract in
response to the
localised current
then that muscle,
or nerve, was
damaged

• Subsequent
muscle
contraction would
allow rapid
recovery from
nerve injury

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Electreat

In 1919 Charles Willie Kent invented a battery-

operated trans cutaneous electrical nerve
stimulation device called “Electreat”.

The Electreat was operated simply by rotating

the roller head of the device over the affected
area and was used for pain relief, including that
suffered by patients with cancer.

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Introducing electrotherapy in clinic
At the same time in England, Reverend
John Wesley was fascinated with
electricity, and was convinced it could be
used to aid physical health and alleviate
human suffering. Combining treatment
with spiritual evangelism, Wesley offered
electrical- based treatments in his London
clinics, and advocated use of electricity as
a treatment for a diverse set of illnesses,
including tuberculosis, epilepsy, and
sciatica

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 treatment of neurological and
psychiatric disorders
Early medical electrical
therapies :
administration of
electric shocks
palsy

were unpredictable and often severe,

including:
Side effects • burns
•convulsions
•cardiac arrests

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Early medical electrical therapies :
administration of electric shocks
Nonetheless, there was some evidence of the
efficacy of this so-called medical cure.
Unscrupulous sales vendors took advantage of
these findings, claiming miraculous cures, although
many of these devices were subsequently found to
be, at best, useless and, more frequently, very
dangerous .

McKee and Johnson’s

quackery and pseudoscience Electricure (1900)

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Electroterapy in 21st Century
• In current medical practice, the use of low-level electrical
energy is now accepted in a range of medical specialities.

• Electrotherapy is also a mainstream treatment choice used

by physiotherapists and for pain management in patients

• Electrotherapy in isolation is rarely the most appropriate

intervention. Whether combined with exercise, manual
therapy or advice and education, it forms part of a package of
care that contributes to the holistic management of the
patient, their family and cares

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Why electrotherapy may have so many
application?

activation
External of
energy Tissue
stimulation physiological
activity

enhancement

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Bioelectric cellular activity
• It is well established that all cells are electrically active,
not just those of the ‘excitable’ tissues.

• The cell membrane has a membrane potential which

averages some 70 mV, and this electrical cell membrane
activity is critical to normal cell function

• By influencing the activity levels of the cell membrane, it

is possible to adjust the ‘excitement’ level in the cell

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 How is possible to modify the
Bioelectric cellular activity?

electromagnetic electrical (e.g.

(e.g. shortwave transcutaneous
therapies, pulsed or electrical nerve
continuous) stimulation; TENS)

electrophysical/mechanical
(e.g. ultrasound)

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Modes of application
• There are two ways in which exogenous energy can be
applied: higher and lower energy

• By utilizing the energy mode that is preferentially

absorbed in the target tissues it is possible to trigger a
range of physiological changes that can be subsequently
employed to achieve therapeutic benefit

• Work is currently aims to utilize the available evidence to

determine the scope and position of the energy,
frequency and amplitude windows

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Higher energy therapies

Force the cell to change its

Electrical ‘excitement levels’ and hence
activity its activity, resulting in
DEPOLARIZATION

Cell membrane
•This mechanism is used in the pain gate mechanism or by causing the release
of endogenous opioids .
•Small Direct Currents (DC) can be utilized to influence the healing responses
of the musculoskeletal tissues and interferential therapy has been employed
to enhance fracture healing

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Low-energy therapies
• In low-intensity therapy the power output light is in the range
of a few milliwatts such as in laser therapy, pulsed short-
wave therapy and ultrasound.
• The aim to increase in cell membrane activity (usually by
influencing a variety of ion gates or channels), and by doing
so, to bring about a change in cell state without overt heating
effects.
• Examples of clinical applications that have demonstrated
significant benefit include tendons, and a range of other
musculoskeletal tissues

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Limitations and prospective

Patient responsiveness

By refining the waveform, signal

amplitude, pulse frequency or
other salient feature of the energy
form, these new therapies offer the
potential to improve the
Personalized medicine effectiveness of the treatment.

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 In summary
• It has been demonstrated that electric energy can be
used in medicine

• It is possible to induce modification in tissue and

cells

• All patients do not answer in the same way to the

therapy, therefore efforts are made to study better
the population, the targets, and the correct type of
electrotherapy to use

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Can we use electric energy to
deliver drugs?

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Pharmacology challenge
Phamacokinetics

Pharmacodynamics

Electric fields is used to deliver drugs and gene to

overcome the cells membrane barrier through
polarization

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Drug Delivery System
• The aim is to deliver molecules into the target,
enhancing efficacy and safety by controlling the rate,
time, and release of the agent

• Biophysical energy such as electric fields, mag- netic

fields, ultrasound and mechanical forces, light and
temperature gradients can act as enhancers for drug
delivery

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Dr. Giulia Malaguarnera and Dr. Michele Vecchio
Different physical energy modules used for drug delivery

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Photodynamic therapy

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Magnetic nanoparticle

•cytotoxic drugs
chemotherapy
•DNA for gene
delivery

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Magnetic drug and gene targeting:
magnetoporation

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Electric field drug and gene delivery:
electroporation

•Cancer treatment,
vaccination and wound
healing
•It has been tested in a
clinical trial of
interleukin-12 plasmid
delivery for melanoma

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Electric field drug and gene delivery:
iontophoresis
Iontophoresis has been
proposed for numerous uses,
including the delivery of local
anesthetics before skin
procedures in children thus
avoiding injections, local drug
delivery for agents such as non-
steroidal anti-inflammatory
drugs (NSAID) or
corticosteroids for
musculoskeletal inflammatory
disorders

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Parameters affecting the efficiency of
iontophoresis
• Several parameters affect the transdermal
absorption of drugs through iontophoresis including:
1. concentration of drug;
2. polarity and ionizable property of drugs;
3. pH of donor solution;
4. co-ions availability;
5. electrode polarity.

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Light induced gene and drug delivery:
optoporation

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Temperature induced drug and gene delivery:
thermoporation and photothermal therapy
• Photothermal therapy (PTT) takes advantage of the excited PS
releasing vibrational energy in the form of heat.
• When lasers are used as the activation source several factors
need to be considered for efficacy:
– tissue absorption coefficient,
– the sensitization of the tissue;
– time/duration of the laser exposure;
– tissue thickness.

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Temperature induced drug and gene delivery:
thermoporation and photothermal therapy

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Acoustic-mediated drug delivery: sonoporation
(Mechanoporation), phonophoresis, sonodynamic therapy

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Theranostic nanoparticles

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 S. Lakshmanan et al. Advanced Drug Delivery Reviews (2014)

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Dr. Giulia Malaguarnera and Dr. Michele Vecchio
Evidence Based Medicine

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Challenge in experimental research
Amplitude

Frequency Energy

The fundamental problem with research in this area is that many investigations only
manipulate the effects of a single variable. For this concept to be fully realised, it is
essential to manipulate the interaction of two or more variables simultaneously –
something which is very difficult in experimental research.

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Focusing on Transdermal drug delivery
ADVANTAGE
• Transdermal drug delivery offers
significant potential for the non-
invasive administration of
therapeutic agents.
• It avoid the hepatic first-pass
effect
• The skin provides a large,
accessible surface area.
• an improved onset time and also
a more rapid offset time—that is,
once the current is switched off,
there is no further transport
Dr. Giulia Malaguarnera and Dr. Michele Vecchio
DISADVANTAGE
• The principal disadvantage is
that the skin’s homeostatic
and protective functions have
ensured that its outer-most
layer, the stratum corneum
(SC), has evolved into a
formidable barrier membrane
• Compromising the skin
barrier function is possible to
assist to concomitant skin
irritation
 Iontophoresis: the most used
transdermal drug delivery system

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

 Pain Managment: Neurodegenerative
•Opioids conditions : Dermatological
•NSAIDS •Parkinson’s and applications
•Local anesthetics Alzheimer’s disease
•Migraine

Cancer

Others:
•Antiemetic Drugs Iontophoresis
•Calcitonine
•Vasopressine Antiviral agents
•etc

Steroids
Ophthalmological Cardiovascular
applications agents
Diabetes: insulin delivery

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Application in ophthalmology:
keratoconus

Riboflavin

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Tissue distribution of dexamethasone
after iontophoresis at the knee

Glass et al.

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Example of Cardiovascular agent:
metaprolol

Zakzewski and Li

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Tacrine: Alzheimer Disease

Kankkunen et al.

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Insulin

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Dr. Giulia Malaguarnera and Dr. Michele Vecchio
www.clinicaltrial.gov

Dr. Giulia Malaguarnera and Dr. Michele Vecchio

Thanks for you attention

giulia.malaguarnera@live.it

Dr. Giulia Malaguarnera and Dr. Michele Vecchio