Reference ↗
Title	Effect of intravenous high dose Vitamin C on postoperative pain and morphine use after laparoscopic colectomy: A randomized controlled trial
Topic	Vitamin C
Author	Jeon, Y, Park, J, Moon, S, Yeo, J
Year	2016
Journal	Pain Research and Management
DOI	http://dx.doi.org/10.1155/2016/9147279

Study Note

Brief summary

In this study, colorectal cancer patients were examined in the first 24 hours after surgical removal of the colon. One group received an additional intravenous injection of vitamin C during the operation and the other group only a placebo. The vitamin C group reported less pain at rest after the operation (both groups reported similar pain ratings during coughing) and two hours after the operation the vitamin C group needed less morphine. This difference disappeared 6 and 24 hours after surgery. Apart from this, the vitamin C group needed fewer additional opiates postoperatively. The two groups did not differ in terms of perceived fatigue, reported nausea and vomiting and length of hospital stay after surgery. A major criticism of this study is that in most cases the authors did not indicate whether the patients differed in terms of the characteristics examined at the beginning of the study. For example, when recording pain, it is important to know whether the patients had a generally high or low sensitivity to pain.

In dieser Studie wurden Darmkrebspatienten in den ersten 24 Stunden nach der operativen Entfernung des Dickdarms untersucht. Eine Gruppe bekam während der Operation zusätzlich intravenös Vitamin C gespritzt und die andere Gruppe nur ein Placebo. Die Vitamin C Gruppe berichtete nach der Operation im Ruhezustand weniger Schmerzen (Während Husten gaben beide Gruppe ähnliche Schmerzeinstufungen an) und zwei Stunden nach der Operation brauchte die Vitamin C Gruppe weniger Morphium. Dieser Unterschied verschwand 6, bzw. 24 Stunden nach der Operation. Abgesehen davon brauchte die Vitamin C Gruppe weniger zusätzliche Opiate postoperativ. Die beiden Gruppen unterschieden sich nicht hinsichtlich der eingeschätzten Erschöpfung, der berichteten Übelkeit und Erbrechen und der Aufenthaltsdauer im Krankenhaus nach der Operation. Ein großer Kritikpunkt an dieser Studie ist, dass die Autoren in den meisten Fällen nicht angegeben haben, ob sich die Patienten hinsichtlich untersuchter Merkmale schon zu Beginn der Studie unterschieden haben. So ist es z.B. bei der Erfassung der Schmerzen wichtig zu wissen, ob es Patienten mit einer generell hohen oder niedrigen Schmerzempfindlichkeit sind.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Monocentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	Colon cancer patients aged 20 to 75 years, scheduled for elective laparoscopic colectomy under general anesthesia
Exclusion criteria	Patients with history of allergy to systemic opioids, substance use disorder, coagulopathy, chronic opioid use, sleep apnea, and analgesic use within 24 h
N randomized	100
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis, ITT Analysis
Specifications on analyses
Countries of data collection	Korea South
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Baseline (pre-/peri-op) T1: 2h post-op T2: 6h post-op T3: 24h post-op

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	NI
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Colorectal Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	NI
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Surgery
Specifications on cancer therapies	Elective laparoscopic colectomy
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Per group - placebo: 29 male, 21 female - intervention: 28 male, 22 female
Age groups	Adults (18+)
Age groups specification	Mean (SD) per group: - placebo: 64.5 (10.6) years - intervention: 65.4 (9.6) years

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	49
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	1
Drop-out reasons	Not arm specified: complications (anastomotic leak and additional ileostomy)
Intervention	Ascorbic acid
Dosage and regime	50mg/kg (ascorbic acid 10 g/20 mL) mixed with normal saline for a total injection volume of 50 mL; intravenous, 30 minutes
One-time application	Yes
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	1
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	48
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2
Drop-out reasons	Not arm specified: complications (anastomotic leak and additional ileostomy)
Intervention	Saline 50 mL
Dosage and regime	Intravenous, 30 minutes
One-time application	Yes
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	1
Side effects / Interactions	NI

Outcomes

<ul><li>"Postoperative opiate consumption" is not in the list (Anorexia/Cachexia, Anxiety, Appetite, Cerebral oedema, Cognitive functioning, Cognitive impairment, Depression, Dermatitis, Distress, Dysgeusia, ...) of allowed values for the "Outcome name" property.</li> <li>"Others" is not in the list (AQoL-8D (Assessment of Quality of Life), ASAT (Auditory Sustained Attention Test), BIA (Bioelectrical impedance analysis), BPI-SF (Brief Pain Inventory - Short Form), CTCAE (Common Terminology Criteria of Adverse Events), ESAS (Edmonton Symptom Assessment Scale), FAACT (Functional Assessment of Anorexia-Cachexia Therapy), FACIT (Functional Assessment of Chronic Illness Therapy), FLIE (Functional Living Index for Emesis), Genitourinary atrophy self-assessment tool, ...) of allowed values for the "Type of measurement" property.</li></ul>

<ul><li>"Frequency of rescue analgesics" is not in the list (Anorexia/Cachexia, Anxiety, Appetite, Cerebral oedema, Cognitive functioning, Cognitive impairment, Depression, Dermatitis, Distress, Dysgeusia, ...) of allowed values for the "Outcome name" property.</li> <li>"Others" is not in the list (AQoL-8D (Assessment of Quality of Life), ASAT (Auditory Sustained Attention Test), BIA (Bioelectrical impedance analysis), BPI-SF (Brief Pain Inventory - Short Form), CTCAE (Common Terminology Criteria of Adverse Events), ESAS (Edmonton Symptom Assessment Scale), FAACT (Functional Assessment of Anorexia-Cachexia Therapy), FACIT (Functional Assessment of Chronic Illness Therapy), FLIE (Functional Living Index for Emesis), Genitourinary atrophy self-assessment tool, ...) of allowed values for the "Type of measurement" property.</li></ul>

Pain

Outcome type As specificed by the authors	Primary
Outcome specification	At rest and while coughing Pain at 2h, 6h and 24h
Type of measurement	NRS (Numeric Rating Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Estimated mean (SD) from graphic: 2, 6 and 24h post-op: at rest significantly lower in intervention compared to placebo; p's<0.05 (no values reported, only graphs) While coughing: no significant difference at any time point; p's>0.05

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Additional medication

Outcome type As specificed by the authors	Primary
Outcome specification	Consumption in mg at 2h, 6h and 24h
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Morphine use (in mg) at 2h was significantly lower in intervention arm (p<0.05), no significant difference between the two arms at 6h and 24h (p's>0.05).

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Fatigue

Outcome type As specificed by the authors	Secondary
Outcome specification	Fatigue at baseline and at 2h, 6h and 24h
Type of measurement	NRS (Numeric Rating Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No difference between groups in postoperative fatigue scores (p's>0.05)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Additional medication

Outcome type As specificed by the authors	Secondary
Outcome specification	Frequency of postoperative rescue analgesics
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	?
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Rescue analgesics were required more frequently in the placebo arm; significant difference compared to intervention arm (p = 0.00). Frequency as Mean(SD): Intervention: 0.8(0.8) Placebo: 1.4(1.0)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	NI
Conflicts of Interest	According to authors no conflict of interest

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis
- Reasons for insufficient sample size based on power analysis
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

Large sample according to power analysis, double-blinded, exact results could only be taken from the graph, no information on whether the arms differed in terms of pain perception at the beginning of the study, only the difference between A and B was considered at all time points, no development over time

PRO

Ethics vote
Adequate randomization
Double blinding
Sample size according to power analysis
Low dropout

CONTRA

Except fatigue, no baseline values for investigated outcomes (e.g. pain), group differences possible
Multiple testing (no models over time)
Poor report quality (figures for endpoints can only be taken from graph)