University of Medicine and Pharmacy [617020]

University of Medicine and Pharmacy
“Iuliu Hațieganu”
Cluj-Napoca
Faculty of Medicine

LICEN CE THESIS

New strategies for post –
operative pain treatment
Coordinator :
Asis. Univ. Dr Mihaela ENE -COCI Ș
Graduate :
Gregor Alexander JACOB 2019

SEITE 1 Inhalt
Introduction ………………………….. ………………………….. ……………………….. 1
1.1 Pain and Physiopathology ………………………….. ……………………… 2
1.1.1 Neurobiology of Pain ………………………….. …………………….. 9
1.1.2 Transduction of Pain ………………………….. ……………………… 11
1.1.3 Transmission of Pain ………………………….. …………………….. 11
1.1.4 The Dorsal Horn ………………………….. ………………………….. . 12
1.2 Ef fects of Pain on body homeostasis ………………………….. …….. 13
1.2.1 Pain Evaluation ………………………….. ………………………….. …….. 14
1.3 Treatment of Pain ………………………….. ………………………….. …….. 16
References ………………………….. ………………………….. ………………………… 31

Introduction

Postoperative pain treatment c omprises an important part of
perioperative patient care and has developed into a subspecialisation
of modern anaesthesiology.
The general objective of postoperative pain management is to
achieve maximal relieve of pain, while keeping side effe cts to a
minimum. Proper pain management is most important for patient care,

SEITE 2 as pain affect s both physical and mental state of the patient , making
it such an important factor for overall well -being and minimising
complications. In the sense of article 5 of the universal declaration of
human rights, “no one shall be subjected to torture or to cruel,
inhumane or degrading treatment or punishment”, postsurgical pain
relief is a human right.

Latest guidelines recommend the use of pharmacologic agen ts as the
standard treatment, using NSAIDs and Opioids via patient control.
This form of treatment includes various side effects including
addiction. To keep those side effects to a minimum we are looking at
alternative treatments which are non -pharmacolo gic, with the goal of
reducing NSAID – and Opioid -use.
Transcutaneous electric nerve stimulation (T ens) is a poorly studied
non-pharmacological alternative which may or may not reduce
postoperative pain to a minimum .
Few studies have been conveyed about u sing Tens in this department.
Therefore, the evidence is too small to evaluate its efficacy and its
importance in postoperative pain treatment and further studies must
be conducted.

1.1 PAIN AND PHYSIOPATHOLOGY
Pain is an unpleasant, complex sensory experience, associated with
actual or potential tissue damagei. It is defined as the psychical
adjunct to an imperative protective reflexii.

SEITE 3 Pain is classified into 2 types, fast and slow or acute and chronic . Fast
pain requires 0.1 sec for the tran smission in contrast to slow pain,
which is felt after 1 sec or moreiii.
Acute pain is self -limiting whereas chronic pain can outlast the
stimulus of pain and the time required for healing, resulting in a
permanent painiv.
The stimul us for pain is transmitted over nociceptors , which are
responsive to mechanical, chemical and thermal stim uli. There are 3
ascending pathway s in the cord and brainstem that differ for the 2
types of pain, we speak of the dual pain pathway : the
neospin othalamic tract for fast pain a nd the palaeospinothalamic
tract for slow pain , and a third diffuse pathway the
archisp inothalamic tractv.
Fast pain signals are transmitted from the peripheral nerves to the
spinal cord by small type A-delta fibres at a speed o f 5-30 m/s ,
whereas slow pain is transmitted by type C fibre s at a speed of 0.5 –
2 m/s .
Type A -delta fibres terminate mainly in the lamina margina lis of the
dorsal horn of the spinal cord, where they further excite the
neospinothalamic trac ts.
Type C fibres terminate in t he substantia gelatinosa of the dorsal
horn of the spinal cord , where thy further excite the
palaeospinothalamic tracts .
The neo spinothalamic tra ct arises from the lamina marginals of the
dorsal horn of the spinal cord and immediately crosses through the

SEITE 4 anterior commissure to the o pposite side, forming the lateral
spinothalamic tract , to then ascend to 3 different termination points:
1. the reticular areas of the brainstem, where few fibres termin ate.
2. the ventrobasal complex of the thalamus , where most fibres
terminate, only a few fibres pass to the
3. the posterior nuclear group of the thalamus
From these 3 termination points, signals are further transmitted to
other basal areas of the brain and to the somatosensory cortex.
The palaeospinothalamic tracts arise form lamina 5 of the dorsal
horn of the spinal cord , which is connected one or more short fibre
neurons to laminae 2 and 3, where it receives its stimuli from. Arising
in lamina 5 the tracts then cross to the opposite side via the anterior
commissure and join the neospinothalamic pathway, upward to the
brain forming the anter olateral pathway.
This dual pathway system is the reason why a short pain stimulus is
often followed by a second pain sensation caused by the slow
pathway, resulting in a “double” pain sensation.

SEITE 5
The archispinothalamic tract is a multisynaptic diffuse tract and is
phylogenetically the oldest tract that carries noxious information. The
first-order nociceptive neurons make synaptic connections in
substantia gelatinosa and ascend to laminae 4 to 7. From lamina 4 to
7, fibres ascend and descend in the spinal cord via the multisynaptic

SEITE 6 propriospinal pathway surrounding the grey matter to synapse with
cells in the MRF -PAG area. Further multisynaptic diffuse pathways
ascend to the intralaminar areas of the thalamus and send collaterals
to the hypothala mus and to the limbic system nuclei. These fibers
mediate visceral, emotional and autonomic reactions to painvi.

We differentiate acute from chronic pain, but also categorize pain
depending on the source :
1. Somatic pain
2. Visceral pain
3. Thalamic pain
4. Neuropathic pain
5. Psychosomatic pain
6. Referred pain
7. Phantom (illusory pain)
Pain is encoded by 3 major groups of somatosensory receptors which
are categorized according to the specific sensation. The major groups
are mechanoreceptors , thermoreceptors and nociceptors .
Mechanoreceptors are for touch, proprioception and further
subdivided into 6 different types, depending on the pressure or
proprioceptive quality they encode. Mechanoreceptors are described
according to their location in th e skin or muscle, the type of adaptation
they exhibit, and the sensation they encode

SEITE 7 1. Pacinian corpuscles are located subcutaneously,
intramuscular and adapt very rapidly (fastest adapting
mechanoreceptor) , encoding vibration and tapping.
2. Meissner’s corpusc les are located in non -hairy skin (fingertips,
lips), adapt rapidly and encode point discrimination, tapping
and flutter. They have small receptive fields that can be used
for two -point discrimination.
3. Hair follicle receptors are arrays of nerve fibres sur rounding
the hair follicles . When the hair is displaced, it excites the hair
follicle receptor. These receptors are adapting rapidly and
detect velocity and direction of movement across the skin.
4. Ruffini’s corpuscles are located in hairy skin, adapt slowly and
encode stretch and joint rotation. These receptors have large
receptive fields. The receptors fire rapidly when the skin is
stretched and then slowly adapt to a new l evel of firing that
corresponds to the intensity of the stimulus
5. Merkel’s receptors a re found in non -hairy skin, they adapt
slowly, have small receptive fields and detect vertical
indentations of the skin. Their response it proportional to
stimulus intensity.
6. Tactile discs are similar to Merkel’s receptors, but found in
hairy skin, rather than non -hairy skin.

Thermoreceptors detect changes in skin temperature, they adapt
slowly a nd there are 2 classes of receptors, cold and warm
receptors . Each receptor has its own range of temperature i t detec ts,
outside of which the recep tors become quiescent.

SEITE 8
Cold receptors detect skin temperatures below 36°C , warm
receptors detect temperatures above 36°C .
The receptors have an overlap in the moderate temperature range,
but they become inactive towards the dominant receptor, for the
current skin temperature range .
In case of extreme temperature s (above 45°C or extreme cold) , warm
or cold receptors turn inactive and do not signal pain . Polymodal
nociceptors will be activated .
Transduction of warm temperatures involves transient receptor
potential (TRP) channels , which are activated by compounds of the
vanilloid class such as capsaicin.
Transduction of cold temperatures involves the TRPM8 channel,
which responds to compounds like menthol.

SEITE 9 Nociceptors respond stimuli that can produce tissue damage , there
are two major classes that also differ in their nervous fibre supply .
Thermal or mechanical nociceptors (TRPV or TRPM8 channels)
respond to s harp, pricking stimuli and are supplied by my elinated A –
delta afferent nerve fibres. Polymodal nociceptors respond to high –
intensity mechanical, chemical and hot and cold stimuli.
Tissue damage releases a variety of chemicals which initiate the
inflammatory response. The resulting local oedema leads to a
histamine release by the injury surrounding mast cell. Those
histamines directly activate nociceptors . In add ition, nociceptor axon s
release sub stances that sensitize the nocicepto rs to stimuli that
previously weren’t noxious or painful . This hyperalgesia leads to the
phenomenon of reduced threshold for pain.

1.1.1 NEUROBIOLOGY OF PAIN

Sensitivity
Nociceptors exhibit sensiti sation after being stimulated
repeatedly ,there can reduction in threshold and therefore an
increase in response to a stimulus or spontaneous activity1.
This sensitization is a result of the actions of bradykinin ,
prostaglandins and several inflammatory mediators, working
as a second messenger system .2 These effects seem to be
specific to different groups of nociceptors and responsible for
the ca use of hyperalgesia2.

SEITE 10 Sleeping nociceptors
Not all nocicep tors are normally activated and only become excitable
under pathological circumstances, like inf lammation2. These are
termed sleeping or silent nociceptors and were first described in joint
tissue3 and have subsequently been found in cutaneous and visceral
tissue.
Pharmacology
At the site of injury, various chemicals are released into the damaged
tissue cells .
Bradykinin, histamine, serotonin, prostaglandins , potassiu m and
protons are released into the d amaged tissue by vascular origin
and mast cells. These chemicals induce nociceptive reaction
or can modify nociceptors by direct activation or by
sensitization.
The primary afferent nerve fibres contain several peptides , the profile
changes when a sustained stimulus is applied, or the nerve is
damaged. The roles for some of these peptides are unclear ,
substance P and calcitonin gene peptide though can be
released into the periphery by classic axon reflex .4,5
Substance P is well studied and it s role in neurogenic inflammation
has been shown . Substance P can induce production of nitri c
oxide and causes degranulation of mast cells which will lead to
the releases of histamine, vasodilatation which will then lead to
the release of other algogens (bradykini n, serotonin) and the
activation of macrophages, monocytes, lymphocytes.2
Cytokines are released by phagocytes and have an important role in

SEITE 11 the inflammatory process, activa ting sensory neurons through
different mechanis ms, including the sympathetic nervous
system .
The prostaglandins and leukotrienes are week algogens, playing a
major role in the sensitisation of receptors to other substances.
The action of NSAIDs relies on the mechanism of in hibiting the
production of prostaglandins by inhibiting cyclooxygenase 1
and 2.

1.1.2 TRANSDUCTION OF PAIN

Peripheral depolarization is transmitted to the dorsal horn
predominantly by three classes of neurons, Aβ , Aδ and C fibers.
Aβ fibers are thickly myelinated, have a fast trans mission (80-
120m/s) for a wide range of non -noxious stimuli and depolarize at a
lower threshold than Aδ fibers which are thinly myelinated, therefor e
have a slower transmission ( 35-75m/s) for non -noxious and noxious
stimuli and a higher threshold for depolarization .
C fibers are unmyelinated and therefore have the lowest conduction
rate at 0.5-2m/s and have a wide range of depolarization
thresholds .6
1.1.3 TRANSMISSION OF PAIN
Transduction at the periphery allows the propagation of an action
potential to the dorsal root ganglion a nd then onto the dorsal horn
which is the synaptic terminus. The dorsal root comprises the cell

SEITE 12 bodies of the primary afferents and is an active in maintaining cell
function, regulation its activity and receptor expression . Receptors
are transported in antero – and retro -grade manner, altering the ir
expression in response to depolarization. This allows longer lasting
changes in neuronal characterization and is part responsible for
sensitization . The communication of the afferents with the
surro unding milieu is dynamic and may trigger secondary
mechanisms producing neuronal activation.6
1.1.4 THE DORSAL HORN
The dorsal horn is classically divided into laminae which correspond
to specific afferent nerve terminations6.
Aβ fibers terminate in lamina 3, synapsing with interneurons6.
Aδ fibers in lamina 1 or in lamina 4/5 . Lamina 1 terminations
synapse with interneurons of which 70% are neurokinin 1 (NK -1)
receptor positive and then synapse with projection neurons of the
spino parabrachial pathway6.
C fibers terminate to 70% in lamina 1/2 as peptidergic tyrosine
(TrkA) kinase positive and to 30% in lamina 2/3 as non -peptidergic
isolectin B4 (IB4) positive6.
The afferent synapsing to interneurons allows significant modulation
before finally synapsing to projection neurons . At this point,
neurotran smitters can stimulate neuronal and non -neuronal cells6.
Both excitation and inhibition can take place in the synap tic cleft ,
accredited to its neurotransmitters. Glycine , GABA ( γ-aminobut yric
acid), endocannabinoids and enkephalins complex interaction
provide tonic inhibition to the dorsal horn6.

SEITE 13 Additionally, glycine and GABA can be released from inhibitory
interneurons , which have been activate by glutam ate AMPA/NMDA
receptors on GABA -ergic neurons6.GABA can bin to GABA -A, C
receptors or to G-protein linked GABA -B receptors , to induce rapid
repolarization6.
Enkephalins are released b y activated interneurons and bind to
opioid receptors µ which are located to 70% on primary afferents ,
leading to direct inhibition . These receptors react to exogenous
opioids, making them the main choice in analgesic therapy6.

1.2 EFFECTS OF PAIN ON BODY HOMEOSTASIS
Pain takes its effects on multiple organ systems (respiratory,
cardiovascular, gastrointestinal, urinary, neuroendocrine, metabolic)
and the psyche of the patient; these effects can be reduced by
adequate pain management.
Respiratory changes after e.g. epigastric or thoracic surgery include
reduction of tidal volume (VT), vital capacity (VC), Residual volume
(RV), forced expiratory volume in one second (FEV1) and functional
residual capacity (FRC). As a reflex response the rectus abdo minus
muscle tone increases and limits the diaphragmatic function7. This
may further lead to hypoxemia, hypercapnia, retention of secretion,
and atelectasis pneumonia7.
Cardiovascular changes are mainly due to an increase in
sympathetic tone, leading to tachycardia, resulting in a higher
oxygen demand of the myocardium which may compromise a

SEITE 14 patient with ischemic heart disease. Patients who are at bedrest,
reducing physic al activity due to pain are more likely to evolve deep
venous thrombosis7.
Gastrointestinal and urinary changes involve intestinal, ureteral and
bladder hypomobility7.
Neuroendocrine and metabolic cha nges mainly include the increase
in stress and catabolic hormones and a decrease in anabolic
hormones which leads to sodium and water retention, elevated
blood glucose, free fatty acids, ketone bodies and lactic acid7.
1.2.1 PAIN EVALUATION
Reliable evaluation of pain is a prerequisite for any clinical trial and
pain management.
A reliable acute pain assessment can be done both at rest and
during motion (important for risk and postoperative complications) .
Powerful tools are the one -dimensional numeric rating scales (NRS)
or the visual analogue scales (VAS) , more so than a verbal
categorical rating scale (VRS) .
The evaluation of chronic pain demands multidimensional qualitative
assessment and its impact on physical, psychological and social
functions . The Brief Pain Inventory, McGil l Pain Questionnaire, The
Massachus etts General Hospital Pain Center’s Pain Assessment
Form , Neuropathic pain screening t ools and The initiative on
Methods, Measurement, and Pain Assessment in Clinical Trials are
considered to be reliable and valid tools .
However, the nature of pain make s objective quantification
impossible .

SEITE 15 Before measuring pain through one of the before mentioned tools,
the patient needs to be examined for pain clinically , in form of
present complain and history of present illness. Physical evaluation
is essential , both generally and systemi cally including a neurol ogical
examination and Waddell’s non -organic signs of :
1. Tenderness
2. Stimulation
3. Distraction
4. Regional disturbance
5. Overreaction
To assess the severity of pain, the deduction needs to include pain
history, the character (continuous, intermittent, occasional),
aggravating & relieving factors, associated symptoms and the effect
of the pain on activity and sleep.
Pain History8
1) Where is the pain?
2) How intense is the pain? (
3) Description of the pain (e.g. burning, aching, stab – bing,
shooting, throbbing, etc).
4) How did the pain start?
5) What is the time course of the pain?
6) What relieves the pain?
7) What aggravates the pain?
8) How does your pain affect
(a) your sleep?
(b) your phys ical functions?
(c) your ability to work?

SEITE 16 (d) your economy?
(e) your mood?
(f) your family life?
(g) your social life?
(h) your sex life?
9) What treatments have you received? Effects of treatments? Any
adverse effects?
10) Are you depressed?
11) Are you worried about the outcome of your pain condition and
your health?
Psychological evaluation is crucial in chronic pain management,
effective tools are the Minne sota Multiphasic Personality Inventory ,
Symptom checklist 90, and Million Behavioral Health Inventory , Beck
Depression Inve ntory .

As for assessing acute pain in a post -operative setting , the numeric
rating scale is best suited for the patient’s subjective feeling of the
present intensity of pain and for detecting changes in pain intensity,
which is important in the assessment of treatment effectiveness.9

1.3 TREATMENT OF PAIN
General principles
The latest journal of pain guidelines recommends the usage of
multimodal analgesia over single -modality therapy. A variety of
analgesic medication combined with non -pharmacological treatment

SEITE 17 may have an added or synergistic effect resulting in a superior pain
management, when targeting different mechani sms of action8.
It is recommended to “routinely incorporate around the clock
nonopioid analge sics and non -pharmacologic therapies into
multimodal analgesic treatments” – Guidelines on Management of
Postoperative Pain , The Journal of Pain, Vol. 17 , No.2, 2016
Pharmacological Modalities
The m ultimodal approach uses opioids /opioid derivatives, NSAIDs
and acetaminophen, Gabapentin, and ketamine as systemic
pharmacological therapy next to local, regional , neuroaxial
techniques and nonpharmacological therapies8.
Nonpharmacological modalities
Transcutaneous electric nerve stimulation (TENS), acupuncture ,
massage, cold therapy and others may be used, but aren’t strongly
recommended because of lack of evidence8.
TENS is activation large afferent fibers which triggers a reflex
activation of the descending inhibitory system to reduce
hyperalgesia after the Gate Theory . TENS induces analgesia over
the peri aqueductal gray (PAG), rostral ventromedial medulla (RVM)
pathways and over central spinal cord pathways.10
It was demonstrated in humans that high frequency (HF) TENS
elevates β-endorphins in the bloodstream and Cerebrospinal fluid
(CSF) and methionine -enkephalin in CSF. In the spinal cord HF
TENS produces analgesia by activating GABA -A and muscarinic
(M1 and M3) receptors , having no effect on serotonin or
noradrenergic receptors, in contra st to low frequency (LF) TENS10.

SEITE 18 LF tens is inhibiting PAG -PVM pathway by acting on µ opioid
receptor s in the periphery . In the spinal cord , LF TENS is achieving
analgesia by acting on GABA -A, serotonin 5 -HT2A , 5-HT3 and
muscarinic receptors M1 and M3.10
In animals it was demonstrated that both HF and LF TENS reduce
dorsal horn neuron activity . HF TENS reduces the release of
glutamate , by blocking δ opioid receptors and substance P . In the
periphery LF TENS is activating opioid receptors better than HF
TENS10.
Current state treatment
The WHO proposed a 3-step ladder framework in 1986 which has
been modified to a 4 -step ladder, which is used in reverse for acute
post-operative pain management. The scheme is exhausting
NSAIDs, weak opioids, strong opioids and local anesthetic s.
For non -opioid analgesia, most frequently used is Parace tamol . It is
optimal for mild to moderate pain and is used in combination with
opioids for post -operative pain. The side effects are minimal and the
effect on blood clotting is insignificant. Adults c an receive up to 4g
per da y, the maximum single dose being 1g7.
As for weak opioids , Tramadol and Dihydrocodeine are commonly
used.
Tramado l’s un ique features include inhibiting serotonin and
noradrenalin reuptake, as well as a potentiated analgesic effect,
when associated with a NSAID . Tramadol is used for mild pain and
can be administered enteral or parenteral . Patients older than 1 year

SEITE 19 of age receive 1 -2 mg/kg bodyweight. The maximum daily dose is
400mg7.
Dihydrocodeine ’s properties are similar to Codeine, which is
partially metaboli zed to morphine, depending on the patient’s
genetic makeup. It is used to treat mode rate to severe pain but is not
considered suitable as base treatment for acute postoperative pain .
The adult dose is 1mg/kg bodyweight7.
Treatment with strong opioids mainly comprises Morphine ,
Fentanyl and Oxycodon e.
Morphine is a prototypical strong opioid and the gold standard for
comparison of strong opioids. various routes of administration are
available, parenteral is preferred in the post -operative setting. It’s
active metabolite morphine -6-glucu ronide is excreted by the kidneys;
therefore, renal insufficiency may lead to an accumulation of the
metabolite and a prolonged effect. For systemic analgesia the dose
it 0.1 mg/kg bodyweight and lasts approximately 4 hours7.
Fentanyl is a derivative of Morphine with a potency that is 100 times
higher. Its use is limited to op erating rooms, recovery rooms and
intensive care. It is continuously titrated intravenously until its
desired effect is achieved7.
Oxycodone is one of the most commonly used opioids for severe
postoperative pain, in adults. Oxycodone is administered by titration
(0.05 -0.1 mg/kg every 10-15 minutes) , as a very slow IV bolus (5 -10
mg) or oral (5-10 mg PO) when transitioning from parenteral7.

SEITE 20 Other Non-traditional analgesic drugs include Ketamine ,
Gabapentin and Lidocaine .
Ketamine is a phencyclidine derivative, which acts as a NMDA
receptor antagonist. There are 2 isomers available , the S (+)-
enantiomer and the R (-)-enantiomer. The S (+)-enantiomer, S –
Ketamine being the more potent one, as it has a higher affinity for
NMDA recepto rs. Ketamine is extensively metabolized by
cytochrome P450 (CYP) 3A and CY P2B611.
The main side effects comprise increase in blood pressure and
heartrate . The induction dose for IV administration of S-ketamine is
0.5–1.0 mg/kg, maintenance is achieved by repeated 0.25 –0.5
mg/kg bolus or a constant infusion of 0.5 –3.0 mg/kg/h12.
Gabapentin is an antiepileptic drug which has also been used to
treat peripheral neuropathic pain. However , two recent meta –
analyses13 have show n its effectiveness in reducing postoperative
pain, when administered orally, several hours before surgery in a
dose of 300 -1200mg1415.
Lidocaine is a local anesthetic that produces analgesic effect s when
administered systemically , presumably by blocking sodium channels
in peripheral nociceptors. Lidocaine shortens postop erative ileus and
has a favorable effect on the healing of burns16. The initial d ose can
be 1.5 –1.0 mg/kg in a short -term infusion before surgery, followed
by a continuous infusion of approx. 0.02 mg/kg/min with varying
duration17.

SEITE 21

2.0 Clinical Protocol
High and low frequency Transcutaneous electric nerve
stimulation in urologic laparoscopic surgery
• The study is condu cted at Spitalului Clinic Municipal Cluj –
Napoca, ATI und Urology
Medical Investigators:
Asist. Univ. Dr. Mihaela Ene -Cociș
Conf. Dr. Constantin B odolea
Stud. Gregor Jacob
Stud y responsible :
Asist. Univ. Dr. Mihaela Ene -Cociș – Cate dra ATI 2, Faculty of
Medicine, UMF “Iuliu Hațieganu” Cluj
Clinical Evaluation:
Asist. Univ. Dr. Mihaela Ene -Cociș
Conf. Dr. Constantin B odolea
Stud. Gregor Jacob

SEITE 22 Introduction
Laparoscopic surgery in the domain of urology, offers multiple
advantages such as reduction of blood loss , duration and intensity of
postoperative pain, morbidity and mortality, decrease in
hospitaliz ation time and costs and an increase in patient satisfaction.
Potential causes for pain in laparoscopic surgery , is pain
cause d by the insertion of the trocars, irritation of the diaphragm and
peritoneum cause by the inflation with carbon dioxide and urologic
surgery specific, the manipulation of retroperitoneal or pelvic organs
and spams of the smooth muscle fibers at the level of the urinary
tract.
Conventional post-operative analgesia frequently utilizes opioids,
paracetamol and restrictively NSAIDs (because of their frequent
association with renal dysfunction or risk of post -operative renal
injury) . Secondary effect s of opioids include nausea, vomiting,
respiratory depression , prolonged ileus, prolonged nece ssity of
postoperative monitoring , delay in oral feeding retake and a lowering
in patient comfort.
One alternative in non-pharmacological pain treatment is
represented by transcutaneous electric nerve stimulation (TENS).
TENS delivers pulsatile electric impulses at the levels of the intact
tegument surface . The analgesic effects is based on the “Gate
Theory” , which says t hat the transmition of a pain stimulus which
reaches the dorsal horn of the spinal cord, can be blocked by
simultaneous stimulation of non -nociceptive Aβ Fibers .

SEITE 23 This theory proposes the existence of a ne uron inhibitor at the level
of the spinal cord , which is stimulated by Aβ fibers and inhibited by
stimuli transmission via A δ and C fibers. At stimulation of this
interneuron, opioid endogens (enkephalin) are liberated and act on
the opioid receptors at the level of the medullary synapses, blocking
nociceptive transmission.
For chronic pain management, ongoing studies show favorable
results.
For acute pain management , systematic analysis of randomized
clinical trial has shown weak results in the post-operative setting .
Despite these results, clinical experience has shown the opposite
and further stud ies with better quality need to be performed to prove
or disprove the utility of TENS.
Working Hypothesis:
Usage of transcutaneous electric nerve stimulation (TENS) has
proven its utility in chronic pain treatment and in some forms in
treatment of acute pain , of non -surgical cause . Similar studies exist
which utilized tens for analgesia during Labor, different diagnostic
interventions or for postoperative pain .
Few d ata on the effectiveness in analgesia by tens , utilizing high
intensity and alternating variable frequency, exist. Neither
intraoperative in conjunction with general anesthesia nor in the first
24 hours post -operatively.
Objectiv es:

SEITE 24 1. Evaluation of TENS’ efficacy in acute
intraoperative pain treatment, in urologic
laparoscopic surgery.
2. Evaluation of TENS’ efficacy in acute post –
operative main treatment during the first
24h
3. Evaluation of TENS’ effect in conjunction
with intra – and postoperative opioid
treatment
4. Evaluation of TENS’ effect on incidence
nausea and vomiting, or other side -effec ts

General Methodology:
1. Anest hesia
All patients included in the study will be put under general
anesthesia with OTI.
Anest hesia induction will be affected und the standard with Fentanyl
3 µg/kgc , Lidocaine 1mg/kgc, Propofol 2 -3 mg/kgc and non –
depola rizing myorelaxant.
General anesthesia will be maintained with inhalatory Sevoflurane at
1-1.3 MAC, conform to patient characteristics .
Intra-operative analgesia will be provided with Fentanyl boluses,
2µg/kgc at necessity in case of patient’s increase in cardiac
frequency or an increase of arterial blood pressure >20% in
comparison to the base value . Paracetamol 1g IV and Morphine
0.01 mg/kgc, administered after the extraction of anatomical parts.

SEITE 25 Prophylactic treatment of post -operative nausea and vomiting is
affected by Dexamethasone, 4mg IV during induction and 4mg
Ondansetron IV, 20 minutes before waking.
Studied Patients
Patients eligible for the study will be randomized by QuickCalcs –
GraphPad Pri sm8. 5 groups with 30 patients will be formed
accordingly:
• Lot 1 – patients with Intra -operative TENS application
• Lot 2 – patients with Post -operative 24h TENS application
• Lot 3 – patients with intra – and post -operative 24h TENS
application
• Lot 4 – patient s with 24h TENS sham (placebo) application
• Lot 5 – patients without TENS application (control)

Modalities of TENS utilization in function with the studied
groups
• Lot 1 – TENS will be applied intraoperatively conform to point
d. (intraoperative) and postoperatively as sham
• Lot 2 – TENS will be applied intraoperatively as sham and
postoperatively conform to point d. (postoperative)
• Lot 3 – TENS will be applied intraoperatively conform to point
d. (intraoperative) and postoperatively conform to point d.
(postoperative)
• Lot 4 – TENS will be applied intraoperatively as sham and
postoperatively as sham

SEITE 26 • Lot 5 – Tens will not be applied at all. Pain score and opioid
consumption will be noted every 3 hours.
Application and utilization of TENS
Mode of application of TENS, intraoperative (Lot 1 -4)
– 4 electrodes with the surface area of 75 mmx50mm will be
used
– Electrodes will be placed on the skin at the level of the
dermatomes corresponding to the type of surgery :
o Nephrectomy : the electrodes will be placed at the
level of the T11 -L3 dermatome on the
corresponding side, anterior and posterior along
the median l ine.
o Prostatectomy: the electrodes will be placed at the
level of the L1-L2 and S2 -S4 dermatomes .
– The electrodes will be connected to the device and the
mode of function will be set as followed :
o Intensity:
▪ Intraoperative:
• Modular 30 minutes 10 Hz 50 mA
100 m s
• Pause 30 minutes
• Modular 30 minutes 100 Hz 15 mA
100 ms
• Continued in alternation for t he
whole duration of the surgery
▪ Postoperative:
• SDR 30 minutes 10 Hz 100 m s,
intensity a t the pain limit

SEITE 27 • Pause 2 hours
• SDW 30 minutes 100 Hz 100ms,
intensity a t the pain limit
• Continued in alternation for the first
24h
e. Evaluation of pain/PONV/other adverse effects
• Pain evaluation will be done every 3 hours for the first 24h post
operation using the NRS scale (NRS: 0=absence of pain; 10=
most intense pain imaginable).
• At the beginning of TENS application and after the session
(after 30 minutes)
• Frequency of nausea and vomiting episodes and patient
satisfaction
• Other adverse reactions: irritation of tegument, paresthesia ,
dizzines s, pruritus, etc.
• Post-operative analgesia will be provided with Paracetamol 1g
IV at 6 hours, Morphine 2mg bolus at necessity, at NRS values
over 3
• Total opioid consumption intra and post operation will be noted

Place of study conduction
The clinical study will be conducted by the sections Anesthesia –
intensive Therapy, Urology and operation block at Spitalului Clinic
Municipal Cluj -Napoca
Inclusion and exclusion of patien ts
Subject inclusion criteria:

SEITE 28 • Patients with urological renal and pro static pathology,
indicated for elective laparoscopic surgery
• Patients with risk for anesthesia ASA 1,2,3
• Patients who are conscient, cooperative, oriented in space
and time with GCS=15 points
• Patients with a creatine clearance ≥30ml/minute
Subject exclusion criteria:
• Underage of 18
• Patients with cardiac pathologies and uncontrolled arrythmia
• Patients with a cardiac pacemaker or internal defibrillator
implant
• Patients with a history of epilepsy, dementia or non –
cooperation
• Pregnancy
• Refusal of participation in the study
Withdrawal of subjects :
• Missing con sent for participation in the study
Treatment administration to preselected subjects, processing and
data
Data collection and storage will fall under the rules of confidentiality.
Investigator1 will realize the randomization with the help of a
calculator (noting the patients NID in accordance to the lot he/she has
been assigned) and the application of TENS at the patient level,
independent of Investigator2 who will only realize the anesthesia and
who has no attribute in intraoperative manipulati on of TENS.

SEITE 29 Investigator2 will verify and complete the intraoperative patient data
on the anesthesia observation sh eet with the total consumption of
analgesic opioids which have been administered during operation and
all other medication administered at the end of the intervention .
At the end of the intervention. Investigator1 accompanies the patient
back to the post o perative section , initiates the TENS settings for the
next 24 hours and hands the patients over to Investigator3 who will
adopt the settings. Investigator4 (medical assistant at the patient bed)
who is not involved in the study , will take notes of the pain score at
the established hours , every 3 hours, and at initiation and finish of the
TENS session, conform to the randomization . Inverstigator5 who is
independent and not involved in the stu dy will collect the patient data
at the end of the 24 hours post operation and collect them together
with the patient NID, in the statistical program.
Attributes of the research team:
Investigator1 : (knows the allocation of the research lots)
Inscribes patients with their NID to the research lots, conform
to randomization .
Sets the TENS parameters for the duration of the intervention,
conform to the preselected research lots (L1 -4), starts the first variant
of stimulation before the insertion o f the tro car and stops the
application when the surgical dressing has been finalized.
At the end of the operation, accompanies the patient to the
observation room, sets the TENS device for the next 24 hours and
hands the patient over to Investigator3.
Investigator 2: (does not know the allocation of the research lots)

SEITE 30 Provides anesthesia conform to protocol and signs all
administered medications in the anesthesia observation sheet.
Investigator3: (knows the allocation of the research lots)
Overtakes the patient from investigator1 and continues the
settings according to protocol for the next 24 hours . Noting pain
scores a nd administered analgesics , recorded by investigator4
Investigator4: (independent from research lot allocation)
Notes pain score at the established hours, every 3 hours and
at the initiation end ending of the TENS sessions. Administers
analgesic doses if pain scores exceed 3 on the NRS.
Investigator5: (learns the allocation of the research lots and the end
of the data collection)
Collects the patient data from the observation sheets and
transcribes them into an Xcell data base.

SEITE 31

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i IASP International Association for the Study of Pain

SEITE 34
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