Epidural Morphine for Geriatrics Undergoing Lower Abdominal Cancer Surgery: a Dose Response Study
Phase: PHASE4
Conditions: Age Problem, Abdominal Cancer
Sponsor: Assiut University

  
 
Epidural Morphine for Geriatrics Undergoing Lower Abdominal Cancer 
Surgery: A Dose-Response Study 
 
Clinical Study Protocol 
By 
Muhammad Mostafa Shawqi 1, * [MBBCh], 
February 2020 
Resident of anesthesia, ICU and pain management 
Supervised by 
Sahar Abdel-Baky Mohamed 1 [MD], Essam Sharkawy 2 [MD], and Diab Hetta 1 [MD] 
Affiliations: 
1. Department of anaesthesiology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt. 
2. Department of anaesthesiology, Faculty of Medicine, Assiut University, Assiut, Egypt. 
*Corresponding author at: Assiut University, Faculty of Medicine, Assiut, Egypt. Postal code: 71515. 
E-mail: m.shawqi@med.au.edu.eg  
Conflict of interests: the authors have no conflicts of interest. 
Fund: local departmental fund without receiving any external grant.  
Ethical approval: IRB of Assiut University Faculty of Medicine, No: 17101147.  
NCT number: NCT04316871 

  
 
Background 
Acute postoperative pain is a common complaint for several days after surgery (1). However, 
acute postoperative pain remains even more under controlled in elderly patients, especially those 
with cognitive impairment and malignancy (2,3). Geriatric population is reported to be at higher 
risk for unwanted side effects from analgesic treatments compared to younger patients due to 
different major risk factors such as: decline in organ function, polypharmacy, pharmacokinetics, 
drug sensitivity, and frailty (4). Despite of the higher risk of opioids, especially morphine, 
causing toxicity and adverse effect; they are still the cornerstone treatment of severe acute 
postoperative pain (5). Morphine in those patients is very likely to cause toxicity because of 
accumulation of its active metabolites compared to other opioids with fewer or no active 
metabolites (6). Epidural morphine is an effective route for an effective drug.(7,8) Furthermore, 
unwanted side effects with neuraxial opioids are minor and managed easily.(9) Regarding 
clinical outcomes, clinical studies showed a lot of improvements associated with postoperative 
opioid analgesia (10–12). Now, there is a clinical necessity to achieve the best management of 
acute postoperative pain in elderly patients with the least possibility of adverse side effects. We 
aim in this randomized, assessor blinded, clinical trial at Assuit University to determine the 
optimum dose of epidural morphine for the highest control of acute postoperative pain in 
geriatrics who are planned to have lower abdominal cancer surgery. 
 
 
 

  
 
Aim of the research 
Our primary outcome is total patient-controlled analgesia (PCA) morphine sulphate (MS) 
consumption within seventy-two hours after surgery. Secondary outcomes include pain-intensity, 
measured using visual analog scale (VAS), Ramsay sedation scale (RSS), and nausea, vomiting 
and pruritus scale. Each of all the previous outcomes is to be recorded at 2, 8, 16, 24, 36, 48 and 
72 hours after surgery. 
Research Methods and Procedures  
1- Study Design: randomized, assessor blinded, clinical trial. 
2- Study Setting: Assuit University Hospitals, Anaesthesia and ICU department. 
3- Study subjects: 
A) Inclusion criteria:  
Eligible patients are men and women aged ≥ 60 years, who are planned to undergo lower 
abdominal cancer surgery. Surgeries via infra-umbilical abdominal incision are considered 
eligible such as ovary, bladder, and colorectal surgeries. 
B) Exclusion criteria: 
We excluded patients with contraindications to neuraxial analgesia. The absolute 
contraindications are lack of consent from the patient, elevated intracranial pressure 
(ICP), primarily due to intracranial mass and infection at the site of the procedure (risk of 
meningitis). While the relative contraindications are (13,14): 
• Pre-existing neurological diseases (particularly those that wax and wane, e.g., multiple 
sclerosis). 

  
 
• Severe dehydration (hypovolemia), due to the risk of hypotension. The risk factors for 
hypotension include hypovolemia, age greater than 40 to 50 years, emergency surgery, 
obesity, chronic alcohol consumption, and chronic hypertension. 
• Severe mitral and aortic stenosis and left ventricular outflow obstruction as seen with 
hypertrophic obstructive cardiomyopathy. 
• Thrombocytopenia or coagulopathy (especially with epidural anaesthesia, due to the risk 
of epidural hepatoma. Of note about coagulopathy, the placement of neuraxial block 
requires revaluation. The American Society of Regional Anaesthesia (ASRA) publishes 
updated guidelines that detail timing for neuraxial anaesthesia for patients on oral 
anticoagulants, anti-platelets, thrombolytic therapy, unfractionated, and low molecular 
weight heparin. Review the latest guidelines before proceeding with the procedure. 
C) Groups: 
Patients were randomized (by using a table of random numbers) to one of four groups to 
receive a single dose of epidural preservative-free morphine out of four doses: 0 mg 
(group D); 1.5 mg (Group A); 3mg (Group B) and 4.5 mg (Group D) at the beginning of 
surgery. A total volume of 10 mL was injected; 5 mL of bupivacaine hydrochloride 
0.125% with the previously mentioned study doses of preservative-free morphine diluted 
in 5 mL preservative-free normal saline by the hospital pharmacist. 
D) Sample Size Calculation: 
The sample size will be calculated using G* Power software 3.1.9.2 considering a study 
power of 80% and a significance level of 0.05 to detect an effect size of 0.75 using one-

  
 
way ANOVA test/t-test. Assuming total IV-PCA morphine consumption is the main 
outcome variable, and the maximum total IV-PCA morphine consumption was 12 ± 16 
mg while in healthy controls was 70 ± 35 mg according to previous studies (15-17), the 
estimated minimum required sample size, after assuming 33% dropouts, will be 88 
patients (22 patients in each group). 
Statistical Analysis Plan 
Data will be analyzed using IBM SPSS statistics version 24 for Windows 10. A value of 
P < 0.05 was considered signiﬁcant. The data will be tested for normality using the 
Shapiro‒Wilk test. Normally distributed variables such as age and BMI are presented as 
the means ± SDs and will be compared with ANOVA. When the assumption of normality 
was rejected, the nonparametric Kruskal‒Wallis test for independent samples will be used 
for comparison. Signiﬁcant Kruskal‒Wallis test values will be Bonferroni corrected when 
various time points are investigated and when multiple tests are applied. For data 
presented as counts and percentages, a chi-squared test will be applied.  
Procedure 
A standardised epidural catheter insertion protocol will be followed in all the study groups. A 20-
gauge, open-tip epidural catheter will be inserted into the T9-10 interspace and advanced 5 cm 
into the epidural space while patients are in the setting position. A total volume of 10 mL will be 
injected; 5 mL of 0.125% bupivacaine hydrochloride was mixed with each of the study doses and 
diluted in 5 mL of preservative-free normal saline by the hospital pharmacist. We will not use 

  
 
the test dose of 0.5% lidocaine or 1:200000% epinephrine and will only use Dogilotti’s principle 
for confirmation of correct epidural catheter placement. If there are no rapid onset within 1-2 
minutes of neuraxial sensory block, which will be observed only during the intrathecal delivery 
of the local anaesthetic, the placement of the epidural catheter will be activated. After 30 min, 
the sensory block around the level of T8-T10 will be tested by pinprick. The diluted 
preservative-free epidural morphine studied doses will be identical in appearance to be 
unrecognizable, so neither the patient nor the attending anaesthesiologist could identify the 
administered dose. General anaesthesia will be then induced using 2 mg/kg propofol and 2 
mcg/kg fentanyl. Endotracheal intubation will be performed with rocuronium (0.5 mg/kg), and 
general anaesthesia will be maintained with sevoflurane and rocuronium (0.2 mg/kg on demand). 
Heart rate and mean arterial blood pressure (MAP) will be kept within 20% of the preoperative 
baseline values as determined by the attending anaesthesiologist. Ondansetron (4 mg) will be 
given as an antiemetic at skin closure. At the end of the surgery, muscle relaxation will be 
reversed by treatment with 0.05 mg/kg neostigmine and 0.01 mg/kg atropine. After extubation, 
the patients will be admitted to the post-anaesthesia care unit (PACU) until they are fully 
recovered from anaesthesia. 
Thereafter, the patients will be transferred to the ICU, and a standardised close monitoring will 
be performed for 72 hours to detect early or late respiratory depression. The same doses of 
epidural morphine for each patient will be administered at 24 hr and 48 hr postoperatively.  
 

  
 
Strength points and Limitations 
The main strengths of this study are that it is highly reproducible and addresses the daily clinical 
aspects of epidural morphine in older adults. However, this study is limited by its focus on lower 
abdominal cancer surgeries only; additionally, it is a single centre study focused on unimodal 
analgesia. Therefore, the generalizability of our results is limited. All other systemic analgesics 
are as under-researched as epidural morphine in this age group. Therefore, further studies with 
larger sample on other drugs and on different types of surgeries are needed to tailor adequate 
multimodal pain management protocols with the least risk to the older adults. The study is also 
limited to clinical response and pharmacodynamics of epidural morphine in the older adults and 
did not investigate the pharmacokinetics, which should be examined in future studies. Due to the 
vulnerability of older adults, we included only ASA I and II patients to assess the balancing dose 
of epidural morphine versus age only. The relationship between the dose of epidural morphine 
and common comorbidities in this age group should also be investigated. 
 
 
 
 
 

  
 
References: 
1. 
Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: Results from a 
national survey suggest postoperative pain continues to be undermanaged. Anesthesia and 
Analgesia. 2003 Aug 1;97(2):534–40.  
2. 
Connelly P. The management of chronic pain in older persons. Vol. 46, Journal of the 
American Geriatrics Society. Blackwell Publishing Inc.; 1998. p. 635–51.  
3. 
Schofield PA. The assessment and management of peri-operative pain in older adults. 
Vol. 69, Anaesthesia. 2014. p. 54–60.  
4. 
Popp B P tenoy R. Management of chronic pain in the elderly: phar macology of opioids 
and other analgesic drugs. In: In: IASP TF on P in the E, Ferrell B, Ferrell BA E, editors. Pain in 
the elderly : a report of the Task Force on Pain in the Elderly of the Intern ational Association for 
the Study of Pain. Seattle (WA): IASP Press; 1996. p. 21–4.  
5. 
McKeown JL. Pain Management Issues for the Geriatric Surgical Patient. Vol. 33, 
Anesthesiology Clinics. W.B. Saunders; 2015. p. 563–76.  
6. 
Baillie SP, Bateman DN, Coates PE, Woodhouse KW. Age and the pharmacokinetics of 
morphine. Age and Ageing. 1989 Jul;18(4):258–62.  

  
 
7. 
McQuay HJ MR, Popp B PR. Local anaesthetics and epidurals. In: n: IASP TF on P in 
the E, Ferrell B, Ferrell BA Editors, editors. Textbook of Pain. London: Churchill Livingstone; 
1999. p. 1215 – 32.  
8. 
Viscusi ER. Emerging techniques in the management of acute pain: Epidural analgesia. 
Vol. 101, Anesthesia and Analgesia. Lippincott Williams and Wilkins; 2005.  
9. 
Gwirtz KH, Young J V., Byers RS, Alley C, Levin K, Walker SG, et al. The safety and 
efficacy of intrathecal opioid analgesia for acute postoperative pain: Seven years’ experience 
with 5969 surgical patients at Indiana University Hospital. Anesthesia and Analgesia. 
1999;88(3):599–604.  
10. 
Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in 
high-risk surgical patients. Anesthesiology. 1987;66(6):729–36.  
11. 
Tuman KJ, McCarthy RJ, March RJ, DeLaria GA, Patel R V., Ivankovich AD. Effects of 
epidural anesthesia and analgesia on coagulation and outcome after major vascular surgery. 
Anesthesia and Analgesia. 1991;73(6):696–704.  
12. 
Christopherson R, Beattie C, Frank SM, Norris EJ, Meinert CL, Gottlieb SO, et al. 
Perioperative morbidity in patients randomized to epidural or general anesthesia for lower 
extremity vascular surgery. Anesthesiology. 1993;79(3):422–34.  

  
 
13. 
Hartmann B, Junger A, Klasen J, Benson M, Jost A, Banzhaf A, et al. The incidence and 
risk factors for hypotension after spinal anesthesia induction: an analysis with automated data 
collection. Anesth Analg [Internet]. 2002 Jun [cited 2024 Jul 11];94(6):1521–9. Available from: 
https://pubmed.ncbi.nlm.nih.gov/12032019/ 
14. 
Carpenter RL, Caplan RA, Brown DL, Stephenson C, Wu R. Incidence and risk factors 
for side effects of spinal anesthesia. Anesthesiology [Internet]. 1992 [cited 2024 Jul 
11];76(6):906–16. Available from: https://pubmed.ncbi.nlm.nih.gov/1599111/ 
15. 
Tani A, Vagheggini G, Moretti F, Del Colombo V, Lehle J, Campana S, et al. Binaural 
Beats Reduce Postoperative Morphine Consumption in Older adults After Total Knee 
Replacement Surgery. Altern Ther Health Med. 2021 Mar;27(2):27–30.  
16. 
Brixel SM, Biboulet P, Swisser F, Choquet O, Aarab Y, Nguyen H, et al. Posterior 
Quadratus Lumborum Block in Total Hip Arthroplasty: A Randomized Controlled Trial. 
Anesthesiology [Internet]. 2021 May 1 [cited 2024 Jul 11];134(5):722–33. Available from: 
https://pubmed.ncbi.nlm.nih.gov/33740816/ 
17. 
Palmer CM, Nogami WM, Van Maren G, Alves DM. Postcesarean epidural morphine: A 
dose-response study. Anesthesia and Analgesia. 2000;90(4):887–91.