Effect of Vitamin C on Pain Reduction After an Emergency Department Visit

Emergency department (ED) clinicians often prescribe anti-inflammatory drugs (NSAIDs) to manage acute musculoskeletal (MSK) pain (e.g.: fracture, sprain, back pain). However, even short-term NSAIDs use can have significant gastrointestinal, cardiovascular, MSK and renal adverse effects. For this reason, some patients cannot take or tolerate NSAIDs. Recent evidence has shown that vitamin C has some analgesic and anti-inflammatory properties particularly in postoperative context and prevent specific types of chronic pain. Furthermore, vitamin C is safe and associated with very few adverse events. The primary objective of this study is to determine whether vitamin C can reduce pain intensity during a seven-day period following an ED visit for acute MSK pain.

The investigators propose to compare two groups of patients, one receiving 900 mg of vitamin C to another receiving a placebo, twice a day for seven days. Both groups will consume acetaminophen slow release 650 mg two pills every eight hours regularly. Naproxen 500 mg (NSAID) will be used as a rescue medication if the patient's pain is not relieved. Participants will be ≥18 years of age, treated in ED for acute MSK pain present for less than 48 hours with pain intensity at triage of ≥ 4 on a 0-10 numeric rating scale, and discharged by an ED clinician with an NSAIDs prescription without opioids. The level of pain intensity during a seven-day period will be assessed daily using an electronic or paper diary, as well as pain relief, pain medication consumption, and adverse events. Three months after the injury, participants will also be contacted to assess the presence of chronic pain. The investigators hypothesized that vitamin C will reduce pain intensity and chronic pain development at three months.

This research could provide a safe alternative to patients who are unable to take NSAIDs. It may also contribute to the reduction of the burden associated with chronic pain development.

Background and Importance: Nonsteroidal anti-inflammatory drugs (NSAIDs) have proven their efficacy and compared advantageously to opioids in treating acute musculoskeletal (MSK) pain. However, even short-term NSAIDs use for acute pain management after an emergency department (ED) discharge can have significant gastrointestinal, cardiovascular, musculoskeletal and renal adverse effects. Recent evidence has shown that vitamin C has, in addition to its antioxidant effect, some analgesic and anti-inflammatory properties. Its analgesic effect has been explored mostly in short-term postoperative context or in disease-specific chronic pain prevention, but never after acute pain from MSK injuries, which are often seen in EDs.

Goal(s) / Research Aims: The primary aim is to evaluate the effectiveness of vitamin C in reducing pain intensity during a seven-day period following ED discharge for an acute MSK pain complaint. The secondary aims are to compare both treatment groups for rescue medication use, average pain relief and adverse events during a seven-day follow-up, and at three months for chronic pain incidence.

Methods / Approaches / Expertise: The investigators will conduct a pragmatic five-center, double-blind randomized placebo-controlled trial (RCT) with 546 participants equally distributed in two arms; one group receiving 900 mg of vitamin C and another one receiving a placebo, twice a day for seven days. Both groups will consume acetaminophen slow release 650 mg two pills every eight hours regularly. Naproxen 500 mg will be used as a rescue medication if the patient's pain is not relieved more than one hour after acetaminophen consumption. Participants will be aged ≥18 years, treated in the emergency department for acute MSK injury present for less than 48 hours with a pain intensity at triage of ≥ 4 on a numerical rating scale (NRS) of 0-10, and scheduled for discharge by an emergency clinician with an NSAIDs prescription without opioids. Daily pain intensity during the seven-day period will be assessed via a previously tested electronic or paper diary. In addition, patients will report their daily rescue pain medication use, pain relief, and adverse events. Three months after the ED visit, participants will be contacted to evaluate chronic pain development.

The investigators hypothesized that vitamin C will reduce pain intensity during a seven-day follow-up for ED discharged patients treated for acute MSK pain. This project brings together a committed, multidisciplinary research team composed of five study sites having previously collaborated on large multicenter RCT studies. All required instruments have been successfully used during an ongoing Canadian Institutes of Health Research (CIHR) grant, a non-objection letter from Health Canada has been already requested and the investigators have secured a provider for both study drugs, all this ensuring a rapid study implementation.

Expected Outcomes: The investigators will provide the following outcomes for patients receiving vitamin C and placebo: pain intensity, rescue medication use, pain relief, and side effects for one-week post-discharge and chronic pain incidence at three months. Confirmation of the vitamin C analgesic effect for acute MSK pain could help patients who are unable to consume or are at risk of complications from NSAIDS. It may also contribute to the reduction of the burden associated with chronic pain development.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥ 18 years old
2. Treated in the ED for acute MSK pain present ≤ 48 hours at triage (time to presentation for most acute MSK pain in our previous study)
3. Numerical rating scale (NRS) pain intensity at triage of ≥ 4 on a 0-10 scale
4. Discharged with instructions to take an NSAID for pain (need determined by treating clinicians)
5. French or English-speaking

Exclusion Criteria:

1. Received an opioid prescription at ED discharge
2. Currently using vitamin C supplements
3. Active cancer
4. Currently treated for chronic pain
5. Unable to fill out a diary or unavailable for follow-up
6. Allergy, to milk (lactose in the placebo), vitamin C, acetaminophen or NSAIDs
7. Treated with cyclosporine or warfarin (interaction with vitamin C)
8. Pre-existing oxalate nephropathy, liver cirrhosis or hemochromatosis
9. Pregnant ≥ 20 weeks.