SYNOPSIS

RajivGandhiUniversity of Health Sciences, Karnataka,

Bangalore.

‘COMPARATIVE ASSESSMENT OF FENTANYL AND BUTORPHANOL AS A POST OPERATIVE ANALGESIC IN PATIENTS AFTER SPINAL ANAESTHESIA’

Name of the candidate:Dr. Nishan Mathias

Guide:Dr. Princy Pallaty

Co-Guide:Dr. Prithi Jain

Course and Subject :M.D (Pharmacology)

Department ofPharmacology,

FatherMullerMedicalCollege,

Kankanady, Mangalore – 575002.

August – 2009

RAJIV GANDHIUNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA

ANNEXURE – II

PROFORMA FOR REGISTRATION OF THE SUBJECT FORDISSERTATION

1. / NAME OF THE CANDIDATE AND ADDRESS / DR. NISHAN MATHIAS
P.G. RESIDENT
FR. MULLER MEDICAL COLLEGE, KANKANADY,
MANGALORE – 575002.
KARNATAKA, INDIA
2. / NAME OF THE INSTITUTION / FR. MULLER MEDICAL COLLEGE, KANKANADY, MANGALORE – 575002
3. / COURSE OF STUDY AND SUBJECT / M.D. (PHARMACOLOGY)
4. / DATE OF ADMISSION TO COURSE / May 2009
5. / TITLE OF THE TOPIC:
COMPARATIVE ASSESSMENT OF FENTANYL AND BUTORPHANOL AS A POST OPERATIVE ANALGESIC IN PATIENTS AFTER SPINAL ANAESTHESIA’.

6. Brief Resume of the Intended Work:

6.1. Need for the study:

According to the taxonomy committee of the international association for the study, pain can be defined as ‘an unpleasant sensory and emotional experience associated with actual potential tissue damage, described in terms of such damage’1.

Post operative pain is something which at all times should be treated and never endured. In modern post operative care this means effective relief from pain, suffering, anxiety and sleeplessness. Thus, the outcome of postoperative recovery may be greatly influenced by effective pain management.

Postoperative pain relief reduces the incidence of chest infection, deep vein thrombosis, stress response and sympathetic activity. Inspite of growing advances in the pharmacological approach of pain relief during surgery, relief of pain in the post operative period continues to remain a challenge.

Adverse effects of post operative pain are many but they can be minimized by pain therapy. Patients with significant post operative pain may show insomnia, restlessness, anxiety and helplessness. Further this will cause respiratory, cardiovascular, gastrointestinal, urinary and metabolic complications.

Opioids have been the mainstay of pain treatment for thousands of years, and they remain so even today. Although morphine like alkaloids have been used for analgesia and sedation for centuries, it was only in 1800 that morphine was isolated as an active compound of opium and only in 1853 with the introduction of syringe and hollow needle, did it allow Opioids to be administered in more precise doses.

Several classification systems are available to describe opioids. Opioids can be classified as natural opium alkaloids, semisynthetic opiates and synthetic Opioids. (Tripathi KD, 2008). The natural opium alkaloids are obtained from Poppy plant, papaver Somniferum, which contains two alkaloid derivatives namely, phenantherine derivatives and benziosoquinoline derivatives. Opioids act by acting on the u, k, delta receptors2.

Opioids have a wide spread pharmacological effect on various system. Effects on the CNS include analgesia, sedation, change in mood, drowsiness and clouding of vision. Depression of the respiratory centre, cough centre, temperature centre and vasomotor centers are also affected.

Fentanyl is a synthetic opioid belonging to the morphinan series acting on the ureceptors. Fentanyl is approximately 100 times more potent than morphine. The time to peak analgesic effect after intravenous administration of fentanyl is less than that of morphine with peak analgesia being reached about 5 minutes. Nausea vomiting and itching can be observed after the administration of Fentanyl. Muscle rigidity appears to be more common after administration of bolus doses of Fentanyl 3

Butorphanol on the other hand is a nitrogen substituted 3,14-dihydroxymorphinan compound. Butorphanol is a kopioid receptor agonist and a mixed agonist-antagonist at u opioid receptor. The analgesic effect of 2-3 mg Butorphanol is approximately equal to 10mg of morphine. The major side effects of Butorphanol however include drowsiness, weakness, sweating, feeling of floating and nausea.

This study investigates the efficacy and tolerability of the two drugs with a view to identify the safe and effective post operative analgesic.

6.2 Review of Literature

Fentanyl is a narcotic analgesic which is a phenylpiperidine derivative which due to its wide acceptance, got introduced as a general anaesthetic in clinical practice as Fentanyl Citrate in 1960’s4. Butorphanol is a morphinan synthetic opioid congener belonging to the phenantherene series with a similar profile of action, as pentazocine.

The review of recent studies in postoperative analgesia and the relevance of selected drugs of interest have been elaborated.

R.Verma et al, 2007, compared the analgesic efficacy of butorphanol and fentanyl as an intravenous anaesthesia in cholecystomy. Butorphanol in this study showed better effects than Fentanyl on the emergence time, recovery time, post operative sedation, suppression of sympathetic response to laryngoscopy and intubation5.

Post operative analgesia with contribution of butorphanol and fentanyl in thoracic surgery patients showed improved efficacy of analgesia and reduced adverse effects of fentanyl 6

Butorphanol with thiopentone v/s fentanyl and thiopentone in laryngeal mask insertion study by P.Chari and B.Ghai () showed excellent laryngeal mask airway insertion conditions when compared to fentanyl i.e. success rate of 98% v/s 86% and easy insertion 92% v/s 71%7.

The comparison of epidural analgesic effects ofbutorphanol, fentanyl was also made in the paediatric age group by A. Szabova et al, which concluded, that their effects were equivalent.

P.Malik, 2006, has also compared epidural fentanyl and butorphanol for post operative analgesia showing a higher sedation score in butorphanol, with both being effective and safe as post operative analgesia8.

Butorphanol has been used as a nasal spray in the management of post operative pain by M.Maladkar et al, 2008. The study also showed that it is safe, highly effective and also a well tolerated alternative in post operative pain management9.

These studies portend the use of Butorphanol and Fentanyl as postoperative analgesic, but as there are no firm conclusions derived as yet, this study would help to throw some light in this regard.

6.3 Objective of the Study:

AIM:The aim is to compare the efficacy of a bolus dose of intravenous butorphanol with intravenous fentanyl as a post operative anaglesic.

The objectives of the research are:

1. To assess the various parameters with fentanyl as a post operative analgesic.

2. To assess the same parameters with butorphanol as a post operative analgesic.

3. Compare and find the most efficacious agent of the two.

7. MATERIALS AND METHODS.

7.1 Source of data:

The study will be conducted at FatherMullerMedicalCollegeHospital, Mangalore, and the study period will be from August 2009 to July 2011.

Type of study: Randomized, prospective double blind study.

7.2. Method of collection of data:

Inclusion Criteria:

Adult Patients of either sex, of ASA I or II, falling between the age groups of 20 to 65 yrs presenting for surgery (Elective/Emergency) under spinal anesthesia will be included after obtaining a written informed consent.

Exclusion Criteria:

Patients with a history of Asthma.

Patients with history of Cardiac or Hepatic disorders.

Patients who are taking centrally acting drugs like benzodiazepines, antidepressants.

Patients with diminished mental competence, deafness, visual disturbances which would prevent them to comprehend and use the Visual analogue scale (VAS).

Patients on any other medications like beta blockers.

Pregnant or lactating mothers.

Plan of the study:

Following approval of institutional ethical committee, 60 patients will be taken up for the study. All the patients will be evaluated thoroughly on the previous day of the surgery and a written informed consent will be obtained. Visual analogue scale would be introduced to the patient to record the pain.

Pre-operative investigation:

All patients shall undergo the following investigations:

  1. Haemoglobin.
  2. Random Blood Sugar.
  3. Blood Urea, Serum Creatinine and Serum Electrolytes.
  4. ECG.

All patients will be kept nil per oral over night and will receive 0.1mg/kg oral diazepam on the night before the surgery.

Details of the study:

All patients will be given 0.02 mg/kg midazolam on arrival to the operation theatre. In the operating room, i.v. line will be secured with a 18G cannula and pulse oximeter, non invasive blood pressure and ECG monitors will be connected. Base line heart rate, blood pressure, SpO2 will be recorded before anesthesia and will be repeated at intervals of 5minutes for the remainder of the study.

At the end of the surgery, the patients will be shifted to the postoperative ward and the vital signs and the events during postoperative stay will be monitored. The level of pain would be enquired as they would be asked to record their pain on a scale of 0-10cms with 0 being no pain and 10 being worse pain.

When a score of 3 or more is recorded, the patient would be randomly allocated to the study groups and analgesics administered intravenously. The equianalgesic doses of intravenous butorphanol (20mcg kg-1) and intravenous fentanyl (1.0mcg kg-1) would be given to the respective groups as mentioned below10.

Group / Drug / Dose (mcg kg-1)
A / Butorphanol / 20
B / Fentanyl / 1

The volume of the study drug and the capacity of the loading syringe used would be identical in both the groups (10ml). The drug will be administered intravenously slowly. The observer, patient and staff nurse will be unaware of the nature of the drug being given to the patient. The onset and duration of the analgesia will be noted. The VAS, Sedation score (according to the Ramsay sedation scale), SpO2, respiratory rate, heart rate, systolic and diastolic blood pressure (SBP and DBP) will be monitored at intervals of 1, 5, 15, 30, 60, 120 minutes and so on till the patient has a VAS score equal to or more than 3.

Ramsay Sedation Score:

  1. Patient is anxious and agitated or restless.
  2. Patient is cooperative, oriented and tranquil.
  3. Patient responds to commands only.
  4. Patient exhibits brisk response to light glabellar tap or loud auditory stimulus.
  5. Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus.
  6. Patient exhibits no response.

Patients who did not have pain relief and recorded VAS score more than 3 even after 30 minutes of drug administration, would be considered as ‘failure of analgesia’. The rescue analgesic in such case would be Diclofenac Sodium 50 – 75mg intravenously.

Other drugs that would be kept at hand would be chlorpheniramine for pruritis, naloxone for drug induced respiratory depression, ondansetron for nausea and vomiting, apart from the emergency drugs. The post operative ward will also be equipped with all the necessary resuscitation drugs and equipments.
Statistical Analysis

Data will be analyzed by analysis of variants (ANOVA) and student t-test.

7.3. Does the study require any investigations or interventions to be conducted on patients or other humans or animals?

No.

7.4. Has ethical clearance been obtained from your institution in case of 7.3?

Yes.

8. LIST OF REFERENCES:

1. Merskey H., Bugduk N.: Classification of chronic pain. Descriptions of chronic pain syndromes and definition of pain terms (ed. 2). SeattleWA: IASP press, 1994.

2. Tripathi KD, Essentials of medical pharmacology. 6th Edition, Jaypee brothers, 2008.

3.Gutstein HB and Akil H ‘Opioid analgesics’, chapter 21 in the pharmacological basis of therapeutics, Goodman and Gilman, 11th edition. Brunta LL et al, 2006.

4. Stanley TH, ‘The history and development of Fentanyl series.’ J. Pain symptom manage. 1992 Apr; 7 (3 Suppl.): 53-7.

5. Verma R et al, ‘Total intravenous anaesthesia in laparoscopic cholecystectomy: comparison of butorphanol and fentanyl.’: The Internet Journal of Anesthesiology. 2007 Volume 14, Number 1.

6. Wan Li, ‘Postoperative intravenous analgesia with butorphanol combined with fentanly in thoracic surgery’. Chinaanesthesiology 2008; 109 A1466.

7. P. Chari, B. Ghai , ‘Comparison of butorphanol and thiopentone vs fentanyl and thiopentone for laryngeal mask airway insertion’. Journal of Clinical Anesthesia, Volume 18, Issue 1, Pages 8-11.

8. Malik P et al, ‘Comparative evaluation of epidural fentanyl and butorphanol for postoperative analgesia.’ J Anaesth Clin Pharmacol 2006; 22(4): 377-382

9. M. Maladkar et al, ‘Evaluation of the efficacy and safety of butorphanol nasal spray in the management of postoperative pain.’ The internet journal of surgery. 2008 Volume 16 Number 1.

10. U. Hammad et al, ‘Comparison of butorphanol and fentanyl for balanced anaesthesia in patients undergoing laparoscopic cholecystectomy.’ J Anaesth Clin Pharmacol 2004; 20(3): 251-254.

9. / SIGNATURE OF THE CANDIDATE:
10. / REMARKS OF THE GUIDE:
11.
11.1
11.2
11.3
11.4
11.5
11.6 / NAME & DESIGNATION OF
GUIDE
SIGNATURE
CO-GUIDE
SIGNATURE
HEAD OF DEPARTMENT
SIGNATURE / DR. PRINCY PALLATY
PROFESSOR
DEPT. OF PHARMACOLOGY
FR. MULLER MEDICAL COLLEGE
MANGALORE – 575002
DR. PRITHI JAIN
ASSOCIATE PROFESSOR
DEPT. OF ANASTHESIOLOGY
FR. MULLER MEDICAL COLLEGE
MANGALORE – 575002
DR. PADMAJA UDAYKUMAR
PROFESSOR AND H O D
DEPT. OF PHARMACOLOGY
FR. MULLER MEDICAL COLLEGE
MANGALORE – 575002
12. / REMARKS OF THE PRINCIPAL
13. / SIGNATURE OF THE PRINCIPAL / DR. JAYPRAKASH ALVA
DEAN
FR. MULLER MEDICAL COLLEGE
MANGALORE – 575002

PROFOMA

Name: I.P No:

Age: Sex:M / F

Date: ASA status: I / II

Pre Operative Check up:

Weight: HR: BP: RS:

CVS: RS:

Premedication:

Intraoperative

Anaesthetic drugs:

Other Drugs:

Post operative

Time of arrival:Drug Label:

HR: BP: RR: SpO2Temp:

Remarks:Drugs Used:

1. Nausea & Vomiting1. Diclofenac Sodium.

2. Pruritus2. Ondansetron.

3. CVS effects3. Chlorpheniramine

4. Respiratory effects4. Naloxone.

5. Dizziness, Dysphoria5. Any other (Specify)

6. Shivering

7. Any other (Specify)

Visual Analogue Scale (VAS)

0 5 10

None Worst

Possible

Ramsay Sedation Score (RS Score)

Score Response

  1. Anxious and agitated or restless.
  2. Awake, cooperative, oriented and tranquil
  3. Semiasleep but responds to commands.
  4. Asleep with brisk response to stimuli.
  5. Asleep with sluggish response to stimuli.
  6. No response can be elicited.s

1