Satisfactory Analgesia Minimal Emesis in Day Surgeries

Study Overview
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Brief Summary
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Currently nearly 70% or more surgeries are being done as ambulatory (day care) procedures as they offer significant benefit to the patients as well as to the hospitals. Inadequate pain relief (30%-40%) and nausea-vomiting form the leading factors affecting the quality of care and hence its efficiency. Opioids form the primary modality to treat moderate to severe pain, but can also cause significant nausea-vomiting and other side effects. Although hydromorphone is five times more potent than morphine, in equianalgesic doses they both could provide similar pain relief. They both exert no ceiling effect for their analgesia, and hence incomplete or inadequate analgesia is related to the appearance of side effects. In this study the investigators shall assess the proportion of patients who satisfy the outcome of 'satisfactory analgesia with minimal nausea-vomiting' in ambulatory surgeries, assessed at 2 hours after surgery. Patients would be randomized to receive either morphine or hydromorphone in the surgical recovery area. All personnel involved with the study would be blinded. The investigators will also look to assess the time to discharge and other side effects. This will help to choose the better drug, thereby improving pain relief and side effects, and also the efficiency of health care delivery.

Detailed Description
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There has been an exponential increase in the number of day case surgical procedures also called as ambulatory surgeries (AS), over the last 2 years.(1) Currently around 70% of procedures are being done as AS, with known benefits to patients and hospitals.(2) Its efficiency and cost effectiveness depends upon its organization and delivery of services. Pain and PONV are recognized as the leading factors affecting the quality of services delivered under AS,(1,3) and they affect the recovery, discharge, and overall satisfaction of patients.(4,5) According to literature, postsurgical pain could be inadequately treated in 30%-60% of patients and 30%-40% of AS patients suffer from significant PONV.(3,6,7) It is estimated that a single episode of PONV can prolong the PACU stay by 25 mins,(8) and patients rate PONV to be the most undesirable outcome associated with anesthesia.(4) Despite the increasing use of non-opioid analgesics, opioid analgesics have remained the primary modality in moderate to severe pain.(7) They cause several side effects such as drowsiness, sedation, PONV, itching and respiratory depression. Appropriate selection of opioid medications becomes significantly important to deliver safe and effective analgesia with minimal side effects. Although M has been the most commonly used medication, HM is also being increasingly used.(9) We do not yet know whether HM is more effective than M in AS patients. Both M and HM exert no ceiling effect for their analgesia, and by this nature incomplete or inadequate analgesia is related to the appearance of side effects.(10) Hence clinical effectiveness of opioids, relative to each other, is reflected not just by satisfactory analgesia, but by a combination of 'satisfactory analgesia with limited side effects'. Clinical observation suggests that HM is clinically better by providing superior or equivalent analgesia with decreased side effects.(9) HM is a semi-synthetic morphine derivative that differs from M in its position 6 of the benzol ring, where it has a keto-group instead of a hydroxy group, making it 5-10 times more potent and enhances its distribution to cerebral tissues, making for easier titration.(9) The t1/2 Ke0 (transfer life from plasma to effect site) is 1.6hr - 4 hr for M, compared to 18-38 min for HM.(9,10) It is observed that health care providers may be willing to provide higher dose of HM compared to M in EMU, as its actual quantity of drug is much smaller and therefore appears to cause less concern.(12, 13) Our literature review showed that there are no previous studies comparing these 2 medications in AS patients. The lone systematic review compared various acute and chronic pain studies, in various routes of drug administration.(9) Of the 11 studies identified; only 4 were done in acute pain settings.(13-16) Two of them were done by the same author in ER settings. Chang et al noted that HM reduced the mean pain scores by 1.3 units [95% CI= (-2.2 to -0.5)] compared to M in 198 adults treated in ER.(12,13). However it did not show much difference in geriatric population.14 In perioperative settings, Hong et al studied the difference in nausea between the 2 medications in 50 patients using PCA and found no difference.(15) Rapp et al studied various effects between the 2 medications in 61 surgical patients using PCA. There is not much clarity about their primary outcome; however they found the effects to be similar.(16) Both these studies had smaller sample sizes. The meta-analysis performed demonstrated that the HM does provide better analgesia than M, with a small effect size; Cohen's d=0.266 (p=0.012).(9) Looked at acute pain alone it was statistically significant (p=0.006), compared to chronic pain (p=0.889). It was noted that that there is a definite lack of comparative studies between them in surgical settings.

Official Title
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Most Effective Opioid Analgesia in Ambulatory Surgeries: a Randomized Control, Investigator Blinded, Parallel Group With Superiority Design Study of Morphine Versus Hydromorphone

Conditions
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Pain, Post Operative Nausea and Vomiting

Intervention / Treatment
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* Drug: Morphine
* Drug: Hydromorphone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ambulatory surgeries producing at least moderate pain-such as cholecystectomy, appendicectomy, ovarian cystectomy, inguinal hernia repair, abdominal wall hernias ability to communicate in English. Exclusion Criteria: allergy to M or HM patient on regular chronic opioid medication patient uncontrolled systemic disease severe obesity with a BMI >35 significant psychological impairment history of drug addiction or dependence any planned regional or nerve block other than local anesthesia infiltration patients with confirmed sleep apnea emergency surgeries and urological surgeries

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Morphine<br>Analgesia with equipotent doses of Morphine and Hydromorphone will be administered in titrated doses. Doses are 1ml=1mg of morphine or 0.2 mg of hydromorphone. Potency ratio of 1:5 (M: HM). 0.05mg/kg morphine units (rounding off to the nearest 1 ml or 0.5 ml) | Drug: Morphine<br>* 1st dose: syringe of 0.04mg/kg morphine units (rounding off to the nearest 1 ml or 0.5 ml); with a maximum of 3 mg of morphine equivalents is administered. Repeat doses: 0.02 mg/kg morphine units every 5-10 minutes to titrate for analgesia and side effects (rounding off to the nearest 1 ml or 0.5 ml)<br>* Other names: Sandoz;|
| Active Comparator: Hydromorphone<br>Analgesia with equipotent doses of Morphine and Hydromorphone will be administered in titrated doses. Doses are 1ml=1mg of morphine or 0.2 mg of hydromorphone. Potency ratio of 1:5 (M: HM). 0.05mg/kg morphine units (rounding off to the nearest 1 ml or 0.5 ml) | Drug: Hydromorphone<br>* 1st dose: syringe of 0.04mg/kg morphine units (rounding off to the nearest 1 ml or 0.5 ml); with a maximum of 3 mg of morphine equivalents is administered. Repeat doses: 0.02 mg/kg morphine units every 5-10 minutes to titrate for analgesia and side effects (rounding off to the nearest 1 ml or 0.5 ml)<br>* Other names: Sandoz;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Our Combined Primary Outcome Will be Number of Patients With Same Analgesia Minimal Emesis, as Compared Between the 2 Groups. | Our combined primary outcome will be number of patients with SAME, as compared between the 2 groups. Analgesia will be based on Numerical Analogue Scale for Pain 0-10 (appendix 3), and Post-operative nausea and vomiting will be based on Verbal Descriptive Scale 0-5 (appendix 3). These observations will be made at the end of 2 hrs or before (corresponding to the time of discharge from PACU), by the PACU nurse. | At 2hrs or at the time of discharge from PACU | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Severe Itching | Severe itching measured as visual analog scale score > 5 on a 0-10 Visual Analog Scale, where 0 = no itching, and 10 = worst itching imaginable | At 2hrs or at the time of discharge from PACU | 
| Severe Sedation | Ramsay Sedation Scale 0-6 | At 2hrs or at the time of discharge from PACU | 
| Severe Respiratory Depression | Presence of Respiratory Rate below 10 and/or Presence of Oxygen Saturation <90 | At 2hrs or at the time of discharge from PACU | 
| Patients Requesting Oral Analgesia in the Day Surgery Unit | Use of rescue drug for pain | At 2hrs or at the time of discharge from PACU | 
| Mean Dose of Analgesic Used | For a day surgery case, from the time of hospital admittance to discharge from hospital is an average 5 hours. | 5 hours post-admit to hospital | 
| Patient Satisfaction Score | Patient satisfaction is measured on a 0-10 visual analogue scale, where 0=completely unsatisfied; 10=extremely satisfied | At 5 hours post-admit to hospital | 
| Time to Discharge From PACU | For a day surgery case, from the time out of operating room to discharge from PACU is an average 2 hours. | At 2hrs or at the time of discharge from PACU | 
| Time to Discharge From Hospital | For a day surgery case, from the time of hospital admittance to discharge from hospital is an average 5 hours. | At 5 hours post-admit to hospital |