1 Lithuanian University of Health Sciences
Faculty of Medicine Department of Anesthesiology
Title of the master's Thesis:
OPIOID ANALGESICS (TRAMADOL) FOR PEDIATRIC POSTOPERATIVE PAIN
A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree
Master of Medicine
Lithuanian University of Health Sciences
Author:
Hiba Kassab
Supervisor:
Prof. Dr. Danguolė Česlava Rugytė Kaunas
2019-2020
2
TABLE OF CONTENTS
SUMMARY………....………...3
ACKNOWLEDGMENTS………....…5
CONFLICTS OF INTEREST….………...5
ABBREVIATIONS ……….………...…...6
CHAPTER 1: INTRODUCTION ……….…………...……7
CHAPTER 2: AIMS AND OBJECTIVES………...……….…………...9
CHAPTER 3: LITERATURE REVIEW ………...…...10
CHAPTER 4: RESEARCH METHODOLOGY AND METHODS ……….………...…...19
CHAPTER 5: RESULTS………...…...20
CHAPTER 6: DISCUSSION OF THE RESULTS………...……….………...23
CHAPTER 7: CONCLUSIONS………...……25
CHAPTER 8: PRACTICAL RECOMMENDATIONS………...26
LITERATURE LIST……….………...27
3
SUMMARY
Author name/surname: Hiba Kassab
Research title: Opioid Analgesics (Tramadol) for Pediatric Postoperative Pain
Aim: To find out the prevalence of Opioids prescription to treat postoperative pain in children Objectives:
1. To find out the proportion of patients given opioids for postoperative pain 2. To find out the proportion of patients given Tramadol for postoperative pain
3. To compare the incidence of side effects for the patients given and not given tramadol for postoperative analgesia
Methodology:
The number of pediatric patients that were administered opioids (Tramadol or Morphine) from January 1
stto December 31
st,2018 was collected using registry books of opioid administration of the Department of Pediatric Surgery at the hospital of the Lithuanian University of Health Sciences
(LUHS), Kaunas Clinics. The total number of pediatric surgeries performed on patients under 18 years old from January till December 2018, was based on a computerized program of the pediatric surgery operating room. The ratio of patients prescribed opioids after the operation was calculated relative to the total number of surgical patients admitted to the operating room of pediatric surgery.
A sample of 32 medical file records of pediatric surgical patients given and not given tramadol for postoperative pain relief were retrospectively reviewed for Tramadol associated side effects.
Results:
During the selected period, 3381 surgeries were performed in the department of pediatric surgery of Kaunas Clinics. Opioids (Tramadol and Morphine) were used in 222 surgeries (6,56%). IV tramadol (fixated dose 2mg/kg) was used in 88 (2,60%) surgeries. No PO tramadol was used during the selected period. IV Morphine was used in 122 (3,61%) surgeries and PO Morphine in 12 (0,35%) surgeries only.
Out of 32 retrospectively reviewed patient records, tramadol was given to 22 patients (68,8%),
and the other 10 (31,2%) were not given tramadol. Children from both groups reported postoperative
side effects, a statistically insignificant difference was seen in both groups (p=0,275); from the selected
group of patients that were given tramadol, only nine patients (40,9%) had following nausea, vomiting,
and headache. Seizure and serotonin syndrome were not observed in any patient.
4 A statistically insignificant difference was also found between both groups in postsurgical period urination time (p=0,196), solid food intake (p=0,333), fluid intake (p=0,232) and ambulation (p=0,364).
Conclusion:
1. The frequency of opioid administration was low.
2. Tramadol was administered in approximately 1/3 of all patients, prescribed opioids.
3. From the selected group of patients that were given tramadol, nausea, vomiting, and
headache were the most common, but statistically insignificantly, compared to patients not
given Tramadol. Life-threatening side effects were not observed.
5
ACKNOWLEDGMENTS
I dedicate this thesis to my beloved mother, father, brothers, and uncle Issam Gh. for their constant encouragement and unwavering faith in me. I would like to say a special thank you to my parents Ouhaila and Safi Kassab, for their enormous support, patience, and love during these six years.
Finally, I would like to extend my thanks to my supervisor Prof. Dr. Danguolė Česlava Rugytė, for her guidance throughout this project.
CONFLICT OF INTEREST
The author reports no conflicts of interest.
ETHICS COMMITTEE APPROVAL
The Bioethics Department of Lithuanian University of Health Sciences approved this study; the Committee of Bioethics has granted permission Nr.BEC-MF-399 issued on 2019-05-22.
The service of Coordination of Research and Studies of Lithuanian University of Health
Sciences granted permission Nr.:SPBT-19 issued on 2020-1-20.
6
ABBREVIATIONS
ANSM- National drug safety agency EMA- European Medicines Agency EM- Extensive metabolizer
ESPA- European society for Pediatric Anesthesiology
FDA- Food and Drug Administration GCS- Glasgow Coma Scale
IM- Intermediate metabolizer IR- Immediate Release IV- Intravenous
M1- O-desmethyltramadol M2- N-desmethyltramadol M5- N, O-didesmethyltramadol
MAOI- Monoamine oxidase inhibitors
NSAIDs- Non-Steroidal Anti- Inflammatory Drugs
OSAS- Obstructive Sleep Apnea Syndrome
PM- Poor metabolizer PO- Per Os
SSRI- Selective serotonin reuptake inhibitor
SR- Sustained release SS- Serotonin syndrome TCA- Tricyclic antidepressant Tr- Tramadol
UGT- UDP-glucuronosyltransferase UM- Ultra-rapid metabolizer
VAS- Visual analog scale
7
CHAPTER 1: INTRODUCTION
Pain control in the pediatric population is a challenge for the health care team because of their vulnerability. Physiologic responses to drugs differ from that of the adult population. Tramadol belongs to the class of weak opioid receptor agonists, that is used after failure of pain relief by
nonsteroidal anti-inflammatory drugs (NSAID) and paracetamol, and before use of potent opioid-like Morphine. Tramadol is also used for moderate and severe pain treatment, and as an adjuvant to anesthesia to prolong the analgesic effect.
Tramadol is a prodrug that needs to be bioactivated by the cytochrome P450 (CYP2D6). The fraction of active metabolite O-desmethyltramadol (M1) predominantly influences the safety, efficacy, and effect. The CYPD26 metabolizer represents only 2% of hepatic CYP content in adults, and its expression differs in every individual. Depending on its expression, the benefit and risk ratio can be evaluated. The maturation of the iso-enzyme CYP2D6 occurs in the first year of life (1 month to 1 year).
The most effective and safest method of Tramadol use in acute cases is to prescribe it at the minimal effective dose following the “Start slow, go slow” rule, while in chronic cases, the
prescription is obtained by adapting the dose to CYP2D6 activity.
The weak opioid tramadol can have interactions with other drugs or substances, and the most known is serotonin syndrome. Adverse reactions commonly happen and can range from mild such as headache, nausea, vomiting, constipation, and seizure, to a life-threatening condition like angioedema and respiratory depression, which may cause death if not treated immediately. Abrupt discontinuation leads to Withdrawal syndrome and causes symptoms such as nausea, sweating, diarrhea, tremor, and insomnia; that condition can be avoided by dose tapering.
“Food and Drug Administration” (FDA) published warning boxes that explain the restriction of tramadol use in children in the USA according to the age and to comorbidities after the identification in the last half of century of 9 cases of breathing life-threatening condition from which three deaths in children <18 years old. The three deaths cases occurred after the use of tramadol oral drops.
“European Medicines Agency” (EMA) restricted the use of tramadol in the management of
postoperative pain in children with conditions of compromised respiratory function. “European Society
for Pediatric Anesthesiology” (ESPA) supports the safe use of tramadol in children by applying an
individualized risk-benefit analysis according to age, weight, origin, and comorbidities.
8 The prevalence of Tramadol prescription for acute pain in the pediatric surgical population is unknown. Over several years, tramadol is one of the available analgesics in the department of Pediatric surgery in the Hospital of LUHS. Therefore, the prevalence of tramadol prescription, compared to other available opioids, was the primary interest of this study.
In comparison with other opioids, tramadol use has fewer side effects that can range from mild to life-threatening, such as gastrointestinal symptoms, respiratory depression, angioedema, seizure, Serotonin syndrome, and death if not resolved quickly. Therefore, tramadol associated side effects were the secondary interest of this study
9
CHAPTER 2: AIM AND OBJECTIVES
Aim: To find out the prevalence of opioids prescription to treat postoperative pain in children Objectives:
1. To find out the proportion of patients given opioids for postoperative pain 2. To find out the proportion of patients given Tramadol for postoperative pain
3. To compare the incidence of side effects for the patients given and not given tramadol for
postoperative analgesia
10
CHAPTER 3: LITERATURE REVIEW
For Literature review, searches were conducted using several databases: Medline (PubMed), Pediatric publications, Science Direct, Cochrane, UpToDate, and ResearchGate. An essential part of the articles used was searched with no more than ten years criteria. The search terms used were:
‘Tramadol pediatrics’, ‘Tramadol in children’, ‘Acute Tramadol’, ‘Tramadol toxicity’, ‘Tramadol side effects. The related articles in PubMed were also used.
Tramadol, a weak synthetic opioid, centrally acting by changing the brain and nervous system response to pain. It is used to alleviate mild to moderately severe pain. It is gradually replacing the prodrug codeine that requires to be metabolized to morphine to be effective, because of the fatal respiratory depressions, and life-threatening effects.
The molecular formula of Tramadol hydrochloride is C16H25NO2. Four different
stereoisomers exist and thus, due to the two chiral centers in the cyclohexane ring [1]. It is a white, bitter crystalline, odorless powder that is soluble in water and ethanol.
Compared to other drugs, tramadol is relatively young. It was created in 1962 by a German drug company specialized in pain treatment and brought to market in 1977 under the name of Tramal [2]. It is sold as hydrochloride salt and is promoted in a variety of pharmaceutical formulation for oral, sublingual, intranasal, rectal, and parenteral administration. According to WHO, Tramadol is used alone or in combination with Paracetamol or Ibuprofen to relieve moderate nociceptive pain. [3]
Tramadol has benefits such as reducing the postoperative pain but also has numerous side effects ranging from mild to life-threatening and thus can limit its use.
PHARMACODYNAMICS:
Tramadol analgesic has a dual mechanism of action: an opioid and a monoaminergic effect.
The mu-opioid receptor agonist – tramadol has a weak affinity to the mu-opioid receptor (6000 times thinner than morphine) and even weaker affinity for kappa and delta receptors [4]. Tramadol has a racemic mixture; the (+) enantiomer has two functions; the first one is to act as an agonist of the mu- opioid receptor and the second is the inhibition of the serotonin reuptake, while the (-) enantiomer function is to inhibit norepinephrine reuptake and thus boosting the analgesic effect of mu-opioid receptor agonist [5]. Tramadol act through different pathways that affect the mu receptor,
noradrenergic, serotonergic, and GABAergic pathways [6]. The main metabolite O-desmethyltramadol
(M1) affinity to the mu-opioid receptor is 200-fold higher than that of the parent drug but lower than
that of morphine, and its analgesic effect is twice the parent drug [7,8].
11 Tramadol pharmacodynamic effects that include analgesia and adverse reactions depend on CYP2D6 activity and drug-drug interactions.
The antidote is used to neutralize the toxic effect of a drug. Naloxone, a competitive antagonist of mu, kappa, and sigma receptors, is available in oral and intravenous formulations. It is used to restore the respiratory depression caused by opioids. Naloxone doesn’t fully reverse Tramadol activity [9,10]. Its administration should be repeated because of the shorter half-life (15-30 min) compared to that of Tramadol, and additional measures (e.g., Bag ventilation) are required because the effect of naloxone is not immediate [9,11]. Khan H. L. et al. assumed that naloxone administered to treat tramadol poisoning could increase the risk of seizure. But Eizadi-Mood N. et al., in his systematic review with Meta-analysis, concluded that the risk of seizure was not raised by the administration of Naloxone in case of acute tramadol poisoning; so clinicians should be cautious while prescribing naloxone in the treatment of acute tramadol poisoning [12,13]. In an animal study, Lagard et al. (2017) assumed that in tramadol-induced neuro-respiratory toxicity overdose in Rat, diazepam/naloxone combination has a greater reverse effect of toxicity than naloxone alone.[14]. No study proving that Diazepam/Naloxone combination has a more significant reverse effect than Naloxone alone in human were found.
Tramadol is available on the market in many formulations and may be administered by oral (capsules, drops, dispersible, and sustained-release (SR) tablets), sublingual, intravenous,
intramuscular, subcutaneous, and rectal (suppositories) delivery. It exists as monotherapy or in combination with other non-opioid drugs (e.g., Tramadol /Acetaminophen, and
Dexketoprofen/Tramadol tablets) [1].
The most commonly used is the oral route. Tramadol drops should be administered with caution according to the infant's weight because of the high risk of medication errors that can cause severe adverse reactions [15]. For acute pain treatment, the main rule “Start slow, go slow” must be respected while using tramadol, while for recurrent/chronic pain treatment, a personalized dose adaptation according to CYP2D6 activity is the safest approach. [3]
The lowest effective dose for the shortest period of time is to be used. Many factors should be considered when administering Tramadol to pediatric patients, and they should be closely monitored for side effects or any life-threatening condition when initiating the therapy.
For acute pain, the immediate release (IR) tramadol tablet dose in the adult patients and
adolescents >17 years old is 50 mg every 4 to 6 hours initially and may be increased to 100 mg every 4
to 6 hours because of its relatively short half-life. While in the SR formulation, the active compound is
released over a longer period; thus, the number of administrations can be reduced. The maximum daily
12 dose of tramadol in adults is 400mg/d. In pediatric patients from 4 to 16 years old included, the initial oral dose is 1- 2 mg/kg/d, and the maximum single dose is 100 mg. While the initial pediatric dose PO of morphine is 7-times less than that of tramadol (0,15-0,30 mg/kg) [16] [17]. According to the
information from the International Association of Forensic Toxicologists (TIAFT), in adults, the therapeutic concentration of tramadol is 0,1-0,8 mg/L, the toxic is 1-2 mg/L, and the fatal is >2mg/L.
[17] For pediatric patients, drug dosing should be based on the physiological characteristics of the infant because of the interindividual variability [59].
Chiaretti et al. (1999) showed in his study that continuous infusion of Tramadol has a more significant effect than when it is given in one single dose.[18]
Different routes of tramadol administration exist, it can be administered systemically (Enteral or Parenteral routes) but also locally (caudal or epidural). Krishnadas et al. (2016) performed a
randomized, double-blind study of 60 children undergoing a sub umbilical elective surgery. They were separated into three groups and given an epidural injection of ropivacaine, ropivacaine/tramadol (RT), or ropivacaine/midazolam (RM). The study showed that the group using epidural RT and RM has prolonged analgesic effect and do not have any side effects [19].
Choudhuri et Al. (2008) study showed that the addition of 1mg/kg tramadol to 0.25% bupivacaine 0.5ml/kg considerably extend the duration of adequate caudal analgesia for inguinal hernia surgery in children and thus with no increase in adverse effects. [20]
PHARMACOKINETICS:
Tramadol pharmacokinetics is clearly illustrated in the adult population and limited in the pediatric population [22]. In adults, after oral administration, 95-100% of tramadol is rapidly absorbed in the upper small intestine with a bioavailability of 75 % if a single dose is taken and ~ 90% after repeated doses and that is due to saturation of first-pass hepatic metabolism. Tramadol
pharmacokinetics in children is known, tramadol drops (1,5 mg/kg/kg) are rapidly absorbed after an oral administration with a peak of tramadol concentration at 30 minutes and 4-5 hours for its
metabolite M1 [22].
Tramadol is a prodrug that needs to be bioactivated. Per Os, the drug is rapidly absorbed with a peak serum concentration reached within 2 hours for capsule and 5 hours for sustained-release tablets.
[23]. The estimated volume of distribution is ~ 2.7 L/Kg in adults and higher/variable in children and preterm (~ 4L/kg) [3]. 20% of tramadol body distribution is protein bound.
A large amount of the absorbed tramadol is metabolized in the liver by two pathways: N-
demethylation and O-demethylation, to form the metabolites of tramadol, and by conjugation reaction
13 Twenty-three metabolites have been identified, and the main 3 are M1(O-desmethyltramadol), M2 (N- desmethyltramadol) and M5 (N, O-didesmethyltramadol) metabolites [3,23]. The metabolite M1 is the main active metabolite and the only one with analgesic activity. CYP2D6 mediates O-demethylation, the same enzyme that transforms codeine to morphine, whereas the N-demethylation to M2 is
catalyzed by CYP3A4 mainly and by CYP2B6. Metabolite M1 is inactivated by glucuronidation via UGT2B7/UGT1A8. The final value of CYP2D6 activity is reached at 52 weeks of age when the highest metabolite concentration occurs. [4]
The enzyme CYP2D6 exhibits genetic polymorphism. Four metabolizer phenotypes have been found, poor metabolizer (PM), extensive metabolizer (EM), intermediate metabolizer (IM) and Ultra- rapid metabolizer (UM). The PM has no or small enzyme activity, EM has a regular enzyme activity, UM has more than normal enzyme activity, and IM has lower than normal enzyme activity. More adverse effects can occur with the UM, while very low or none analgesic efficacy is seen in PM and IM, respectively [3]. The inhibition of CYP2D6 activity decrease the analgesic activity executed by M1 formation, so a considerable concentration of the prodrug accumulates and increase the risk of dose-dependent serotonin syndrome
Oral tramadol has a half-life of 6-7 hours, and the half-life of its active metabolite is of 10-11 hours [24]. Tramadol and its metabolites are mainly eliminated by the kidneys from which ~ 30%
unchanged and 60% in the form of metabolites. The remaining drug is removed in the feces [7].
Elimination half-life depends on the CYP2D6 activity and is around 5 hours for tramadol and 8 hours for M1 [25]. The dose should be decreased in case of hepatic or renal impairment because of the prolongation of the elimination half-life. Tramadol and M1 renal elimination are the same for adult and children from 1 year of age but is slowed for children below one year of age because of the lower capacity of renal elimination and the delayed Glomerular filtration rate (GFR) maturation [4,22]. From the 25th postconceptional week, the clearance of tramadol increases rapidly and reaches 85% of the adult value at the 44
thpostconceptional week [26]
PEDIATRIC CLINICAL USE:
Tramadol is generally used for acute, chronic, and cancer pain. In children, it is used for the management of acute nociceptive pain in case of trauma or postoperative settings. Usually, tramadol is used after failure of pain relief by NSAIDs and paracetamol, and before the use of potent opioid-like Morphine. Tramadol can be administered preemptively- before a painful stimulus is generated, and thus the total postoperative analgesic need is decreased.
Maryam et al. (2017) compared the effect on pain of peritonsillar infiltration of tramadol
2mg/kg diluted in normal saline administered before or after tonsillectomy and found out that up to 2
14 hours postoperatively the pain is better controlled by tramadol administered after the surgery and from 8 hours after surgery postoperative pain was better controlled by tramadol delivered before starting the operation.[27]
Prakash et al. (2006) compared three different tramadol doses combined with bupivacaine and administered locally by caudal route in pediatric inguinal herniotomy. The authors concluded that the duration of caudal epidural analgesia is longer with a tramadol dose of 2mg/kg [28]. The duration of postoperative analgesia is prolonged when tramadol is given in addition to bupivacaine for caudal epidural block in children.
In a prospective, randomized, double-blind study, a comparison of postoperative analgesia between two groups of children aged from 1-8 years undergoing major abdominal surgery that were administered respectively iv infusion of tramadol 0,25mg/kg/h alone for 24h postoperatively and iv infusion of tramadol 0,25 mg/kg/h for 24h postoperatively combined to per rectal suppository of paracetamol 90mg/kg/d (first dose 30mg/kg and 20mg/kg every 6h for the next 18h); postoperative pain was better controlled in the second group where iv infusion of tramadol combined with per rectal paracetamol was used [29].
ADVERSE EFFECTS:
In comparison with other opioids, tramadol is an analgesic with fewer side effects. It can cause mild to life-threatening adverse effects such as gastrointestinal symptoms, respiratory depression, angioedema, seizure, Serotonin syndrome, and death if not resolved quickly. Diversity in the response depends on the CYP2D6 genotype, drug-drug interactions, medication error, or abrupt discontinuation.
Tramadol’s serotonin and norepinephrine reuptake inhibitory effect sometimes result in adverse reactions like Serotonin syndrome and seizure [30]. Tramadol overdose increases the risk of seizure; it is dose-dependent and most frequent in the male gender [31]. Ahmadimanesh et Al. investigated the correlation between plasma concentrations of tramadol and its metabolites, and incidence of seizure in tramadol-intoxicated patients, they found in patients who experienced seizures a higher plasma
concentration of tramadol and its metabolites (M1, M2, M5) compared to those who did not [32].
It has been reported that tramadol causes seizures in therapeutic doses and overdosing in adults but
rarely in children, while that was not reported in other studies. Two cases of children’s seizures caused
by continuous infusion of tramadol analgesia in China were published in the Pediatric Anesthesia
Journal in 2012:
15 Case 1: a 2-years-old male weighing 12,5 kg with no previous seizures or any past medical history had a urethroplasty. He was administered postoperative analgesia via intravenous pump containing 0,75 mg/kg/h of tramadol, which was later noticed to be an overdose and 0,125 mg/kg/h of
Granisetron. Four hours later, parents noticed seizure-like symptoms (vertical epileptic gaze, lockjaw, stiffening of extremities). The doctor administered 70 mg of phenobarbital, 4mg of Etomidate, and immediate intubation was performed.
Case 2: a 5-month-old male child weighing 8 kg with no past medical history, underwent a teratoma resection. Postoperatively he was administered via intravenous pump 0,2 mg/kg/h tramadol and 0,5 mg/kg/d Granisetron. Five hours later, the child showed signs of seizure (stiffening of all extremities and vertical epileptic gaze). He was then treated by 5 mg dexamethasone and intensive care. The drug suspected of lowering the threshold of seizure in these cases was Granisetron that was confirmed in a study performed on animals but not on humans [33].
Antiemetics like Ondansetron, Granisetron, and Metoclopramide are commonly used postoperatively to reduce vomiting and nausea effects. ESPA advises against tramadol-
metoclopramide and tramadol-ondansetron combinations as it reduces the efficacy of tramadol by an unknown mechanism and may be associated with serotonin syndrome [34] [53].
In many reported cases, the seizures mostly occurred within the 4 hours following IR tramadol ingestion. In a case report of an 8-month-old boy that ingested 600 mg of ER tramadol (3 tablets of 200 mg), 6h after ingestion the child was sedated with a period of agitation and tachycardia, 10h after ingestion he experienced the first apneic episode and was given 1 mg naloxone and responded
immediately, the second apneic episode happened 15 hours after the ingestion with a 30 seconds tonic- clonic seizure. The child returned to baseline 29h after the intake. [35]
In the case of CYP2D6 enzyme deficiency, accumulation of the parent drug occurs because of the absence of metabolization to M1 in the liver, so the concentration of serotonin in the synaptic cleft occurs, and this cause serotonin syndrome [23,36]. The UM CYP2D6 enzyme leads to high plasma M1 concentration, which can cause complications such as Respiratory depression, oversedation, nausea, and death [8,37]. A case report published in 2015 reported a severe respiratory depression of a five years old boy undergoing an adenotonsillectomy for Obstructive Sleep Apnea Syndrome (OSAS), postoperatively to treat the pain patient received one oral 20mg dose for tramadol and was then found lethargic. Genotyping of the patient revealed the presence of the UM CYP2D6 enzyme [10].
Hypoglycemia is rare but may occur in tramadol overdose, a case report of a 4-year-old boy
that ingested 1,2g (6 tablets of 200 mg) of tramadol an hour before going to the pediatric emergency
department; patient convulsed twice, vomited several times and lost conscience. On examination the
16 15 points Glasgow Coma Scale (GCS) is of 3, bilateral pupils size is 1mm, respiratory rate of 19/min, oxygen saturation in room air of 85% pulse rate of 110 beats per minute, blood pressure 90/60 mmHg, and the random blood sugar is of 2 mmol/l. The patient was administered dextrose infusion and
intranasal oxygen and regained consciousness 7 hours after his admission, and no new seizures were reported [38].
The opioid (Tramadol) metabolized by the cytochrome P450 is associated with many drug- drug interactions that can lead either to a reduction or excess in the opioid effect [39]. Toxicity can happen accidentally, and the main cause of poisoning death is a drug interaction. There are 497 drug interactions in total; it includes 279 major, 215 moderate, and three minor interactions
(Drugs.com/tramadol). Tramadol should not be administered for people on current or recent
Monoamine oxidase inhibitors (MAOI), Tricyclic antidepressant (TCA), anticoagulant, digoxin [9].
Tramadol intake is contraindicated in case of hypersensitivity to opioids, and in concurrent use of drugs that undergo hepatic metabolism.
Table 1- Drug associated with serotonin syndrome Selective serotonin reuptake inhibitors: sertraline, fluoxetine
Antidepressants: clomipramine, phenelzine
Monoamine oxidase inhibitors: clorgiline, phenelzine Tricyclic antidepressants: clomipramine, amitriptyline Anticonvulsant: valproate
Opioids: tramadol, fentanyl Antibiotics: linezolid
Antiemetic: Granisetron, ondansetron, metoclopramide
Concomitant use of tramadol and Selective serotonin reuptake inhibitors (SSRIs) cause
hallucinations and Serotonin Syndrome (SS) in adults. Drugs associated with serotonin syndrome are
presented in Table 1. Serotonin syndrome is a mild to a potentially life-threatening syndrome that
results of an excess serotonin at the 5-HT receptor. It has been reported in all age groups. Findings are
presented as a triad of clinical signs: mental status change (agitation, confusion, delirium, and anxiety),
autonomic hyperactivity (tachycardia, tachypnea, hypertension, hyperthermia, diarrhea/vomiting, and
shivering) and neuromuscular abnormalities (clonus, tremor, the rigidity of muscles and hyperreflexia)
[23, 40]. Hunter Serotonin Toxicity Criteria (HSTC) is used to diagnose SS; a patient should have
consumed a serotonergic drug and have one of the five groups of conditions (Table 2). In children, it is
not always the case because SS can occur in intoxication with tramadol, without concomitant use of
17 SSRIs, as shown in the case report of an 8-month-old girl that ingested accidentally 200 mg of her father’s tramadol tablet. No other drugs were taken, the patient was unable to sleep, agitated, and was admitted to the hospital in the next morning after an episode of epistaxis. The girl developed a
moderate SS. Vital signs showed tachycardia, and the neurological examination revealed reactive pupils, hyperreflexia of lower-limbs, agitation and drowsiness, GCS of 10. 24-hours later, she
developed hyperthermia and hypertension, no seizures or myoclonus were observed. Intoxication was confirmed by a tramadol serum plasma of 680 µg (adult’ normal range 100-300 µg/L). On day 5, the girl was discharged with no sequelae. [41]
The common gastrointestinal side effects of tramadol are nausea, vomiting, and constipation that is caused by decreased gastrointestinal motility and intestinal secretion and thus by acting on the mu-opioid receptors [42, 43]. Constipation is reported less than in morphine use. Gastrointestinal hemorrhage was reported after the co-administration of NSAIDs and tramadol caused by platelet inhibition [44].
Table 2- Hunter Serotonin Toxicity Criteria Presence of serotonergic agent AND
1. Spontaneous clonus
2. Inducible clonus AND agitation OR diaphoresis 3. Ocular clonus AND agitation OR diaphoresis 4. Tremor AND Hyperreflexia
5. Hypertonia AND Temperature >38°C AND clonus (ocular or inducible)
SAFETY:
Advised age for tramadol use is >17 years old for the US while that of Europe is >3 years old.
The EMA and FDA have published safety boxes concerning codeine-containing drugs, especially after discovering the UM. Both agencies advised avoiding the use of codeine-containing drugs to children
<12 years old despite the indications, to <18 years old patients undergoing tonsillectomy or
adenoidectomy for OSAS, moreover for breastfeeding women due to possible harm to their infants.
[45] [46].
FDA also added a recommendation against the use of codeine and tramadol in adolescents between 12 and 18 years who have specific conditions: obese, obstructive sleep apnea, or severe lung disease because that may lead to a life-threatening breathing condition. [46]. If tramadol is
administered to that category of patients, vital signs should be carefully monitored to identify and treat
18 a life-threatening situation. EMA restricted the use of tramadol in the management of postoperative pain in children with conditions of compromised respiratory function while the ESPA supports the safe use of tramadol in children by applying an individualized risk-benefit analysis according to age,
weight, origin, and comorbidities. [56]
The prescription should be avoided in many cases such as sensitivity to tramadol, breathing problems, intestinal blockage, liver or kidney disease, history of epilepsy, mental illness or suicidal attempts, and abrupt combination of drugs that can interact with each other or that may lower the seizure threshold. [7]
Caution is required while prescribing naloxone in case of acute poisoning with tramadol, as
shown in different studies. Depending on the patient's characteristics and history, naloxone can
provoke or increase seizures [12,13,47].
19
CHAPTER 4: RESEARCH METHODOLOGY AND METHODS
1. Prevalence of opioid including tramadol administration in children after general surgery
For the prevalence of opioid and tramadol administration, the number of pediatric patients that were administered opioids (Tramadol or Morphine) from January 1
stto December 31
st,2018 was collected using registry books of opioid administration of the Department of Pediatric Surgery at the hospital of the Lithuanian University of Health Sciences (LUHS), Kaunas Clinics. The total number of pediatric surgeries performed on patients under 18 years old from January till December 2018, was based on a computerized program of the pediatric surgery operating room. The ratio of patients prescribed opioids after the operation was calculated relative to the total number of surgical patients admitted to the operating room of pediatric surgery. The proportions of patients, given intravenous and oral forms of tramadol, intravenous, and oral forms of morphine, were the outcomes of interest.
2. The incidence of side effects for the patients given and not given tramadol for postoperative analgesia
To find out the tramadol associated side effects and their frequency, retrospective analysis of patient records was performed. Patients were included if aged ≥1 and ≤17 years old, ASA physical status classes I and II, who underwent moderate surgeries, and when pain scores (every 8h by 10 point pain scales), time to oral intake and the first urination after surgery, as well as side effects, were noted on postoperative follow-up. Patients that underwent minor surgeries were not included.
Thus, the sample of 32 selected pediatric patients was analyzed retrospectively. All patients were given IV Ketoprofen 1,5mg/kg every 8 hours after surgery. IV tramadol 2mg/kg was given as a rescue medication (on patient request or when VAS >5 according to a 10-point pain scale). Thus, tramadol was given to 22 patients (68,8%) (Tr+ group), and the other 10 (31,2%) were not given tramadol (Tr- group). Also, 11 patients (50%) of Tr+ and five patients (50%) of Tr- group were given IV Paracetamol 20 mg/kg every 8 hours for the first 24 hours after the surgery.
The time between extubation of the trachea after surgery and the first spontaneous urination, oral and solid food intake, and ambulation time in hours were recorded, and side effects (nausea, vomiting, and headache) were noted up till 24h after surgery.
All the data were collected and entered into the computer using the Excel programs for Windows 10
and the SPSS (Statistical Package for Social Sciences). Demographic variables and the outcomes were
presented as median values and the range. The difference between the two groups was assessed by the
Mann-Whitney test and the Chi-square test. For all analyses, the significance level was set at p≤0,05.
20
CHAPTER 5: RESULTS
1. The prevalence of opioid and tramadol administration:
The total amount of surgeries of the three operating rooms present in the department of pediatric surgery of Kaunas Clinics from January 1
stto December 31
st,2018 was 3381 surgeries.
Tramadol and Morphine after surgery were given only to 222 patients (6.56%); Intravenous Morphine was used in n=122/3381 (frequency is 3,61%), while the use of oral Morphine is 0,35%
(n=12/3381). The frequency of iv tramadol is 2,60% (n=88/3381), and no oral tramadol was used in 2018.
2. The incidence of side effects for the patients given and not given tramadol for postoperative analgesia
The demographic and clinical variables of Tr+ and Tr- groups are shown in Table 3. Most patients included in this retrospective study were aged 7-17 years old (Graph 1). Both groups had the same median surgery duration. The majority of patients in both groups had undergone orthopedic surgery, followed by superficial body surface surgery. There are no significant differences regarding patients' characteristics, gender weight, age, type, and duration of surgeries (Table 3).
Table 3- Demographic and clinical variability between Tr+ and Tr- groups
Variable Tr + group1 (N=22) Tr – group2 (N=10) p-value
Gender n (%)
- Female (n=18) - Male (n=14)
14 (63,7) 8 (36,3)
4 (40) 6 (60)
0,758
Weight (Kg) 47,5
(Min- 9, Max- 86) R- 77
47,5 (Min- 17, Max- 72)
R- 55
0,848
Age (Y) 11,5
(Min- 1, Max- 17) R-16
12,5 (Min- 4, Max- 17)
R-13
0,247
Type of surgery n (%)
- Superficial body surface (n=7) - Thoracic and chest (n=1) - Orthopedic (n=21) - Visceral (n=2)
5 (22,74) 1 (4,54) 15 (68,18)
1 (4,54)
2(20) 0(0) 7 (70) 1(10)
0,835♦
Surgery duration (min) 105
(Min- 60, Max- 210) R-150
105
(Min- 60, Max- 190) R-130
0,992
(1) Tr+ Tramadol used; (2)Tr- Tramadol not used; R- Range (Max-Min=R); ♦Chi-square test
21
0 2 4 6 8 10
1-6 yr 7-12 yr 13-17 yr
No. of patients
Graph 1- Age distribution (p-0,247)
Tr + Tr-
Table 4- Outcomes measurement
Tr+ group 1 Tr- group2 p-value
Side Effects Nausea Vomiting Headache
9 patients (40,9%) 8
6 5
1 patient (10 %) 1 1 1
0,275
♦Urination after surgery (h) 4,65 (min-0,5 – max- 24) R-23,5
4,3 (min- 1,8 - max- 12) R- 10,2
0,196
Solid food intake post-surgery (h) 3,25 (min-1,3 – max-21,8) R-20,5
2,45 (min- 1,5 – max-7) R-5,5
0,333
Fluid intake post-surgery (h) 2,4 (min-0,5 – max-6,5) R-6
1,9 (min-1 – max-2,5) R-1,5
0,232
Ambulation (h) 4,28 (min-2,2 – max-24) R-21,8
3,7 (min1,3 – max-24) R-22,7
0,364
Pain score Cumulative/mean
Maximal
2,61 3,75
2,25 5
0,423 0,048 (1) Tr+ Tramadol used; (2)Tr- Tramadol not used; ♦Chi-square test
