a b s t r a c t

Objectives: This randomized clinical trial compares the efficacy and safety of oral oxycodone (an oral opioid) with naproxen (a nonsteroidal anti-inflammatory drug) in Acute pain control in patients with soft tissue injury. It also evaluates the need for additional doses of analgesics in the first 24 hours of discharge from emergency depart- ment (ED).

Methods: Adult (N 18 years old) patients with soft tissue injuries were enrolled in a teaching urban ED. Subjects were randomly allocated to receive a single dose of oral oxycodone (5 mg) or oral naproxen (250 mg). Pain scores and drugs’ adverse effects were assessed before, 30 minutes, and 60 minutes after medication. Outcome: efficacy in pain control (reduction in pain scale N 2 points) and safety (rate of side effects). The need for additional pain medication after discharge was assessed by follow-up phone call 24 hours after discharge.

Results: A total of 150 patients were enrolled. Pain scores were similar in oxycodone vs naproxen groups before (6.21 +- 0.9 in vs 6.0 +- 1.0), 30 minutes (4.5 +- 1.4 vs 4.4 +- 1.2), and 60 minutes (2.5 +- 1.3 in vs 2.6 +- 1.3) after medication, respectively. Twelve (16.0%) patients in oral oxycodone group and 5 (6.6%) patients in naproxen group needed more analgesics in first 24 hours after ED discharge. Adverse effects were more common in oxyco- done group (statistically significant difference). The most common adverse effects in oxycodone group were nausea, (13.3%); vomiting, (8.0%); dizziness, (5.3%); drowsiness, 3 (4.0%); and pruritis, (2.7%).

Conclusion: Oral oxycodone is as effective as naproxen in soft tissue injury pain control but has a less favorable safety profile.

(C) 2015

Introduction

Soft tissue injuries are common entities in the emergency depart- ments (EDs). It is estimated that up to 10% of ED visits are due to soft tis- sue injuries [1]. Pain control is an essential component of management in such cases. In addition to patient’s comfort, adequate pain control may expedite patient’s return to normal physical activity by facilitating early controlled mobilization and exercise.

Healing after soft tissue injury starts with an inflammatory phase. Some of the elements of this Inflammatory process are necessary for healing. Some investigators have suggested that inhibiting this inflam- matory phase by anti-inflammatory drugs may impair the healing

? Conflict of interest disclosure: All authors declare that they have no conflict of interest.

?? Compliance with ethical requirements: This study was approved by institutional

ethics committee, and written informed consent was obtained from all patients. Trial was registered at irct.ir (identifier: IRCT201112208104N3).

? Funding statement: This research received no specific grant from any funding agency

in the public, commercial, or not-for-profit sectors.

* Corresponding author at: Niyayesh St, Sattarkhan Ave, Tehran, Iran, 14456. Tel./ fax: +98 21 66525327.

E-mail address: [email protected] (M. Fathi).

process. Therefore, it might be more appropriate to administer analge- sics without anti-inflammatory properties to avoid impacting the in- flammatory responses [2-5].

Oral oxycodone is an opioid with high oral bioavailability and pre- dictable side effects. It is commonly used in patients whose pain does not respond to Nonsteroidal anti-inflammatory drugs or acet- aminophen alone [6-8].

The objective of this study was to compare the efficacy and safety of oral oxycodone with those of naproxen for treatment of pain in ED pa- tients with soft tissue injury [9].

Methods

Study design

This study was a double-blind noninferiority randomized clinical trial. We enrolled a convenient sample of ED patients with soft tissue in- juries. The study was conducted in a tertiary academic ED with annual census of 30000. The study was approved by institutional ethics com- mittee, and written informed consent was obtained from all patients. The trial was registered with the Iranian Registry of Clinical Trials (http://www.irct.ir, identifier: IRCT201112208104N3).

http://dx.doi.org/10.1016/j.ajem.2015.05.021

0735-6757/(C) 2015

1206 M. Fathi et al. / American Journal of Emergency Medicine 33 (2015) 1205-1208

Table 1

Baseline data of patients in 2 regimen groups

Variable	Oxycodone		Naproxen
	(n = 75)		(n = 75)
Age, mean (+-SD), y Sex, n (%)	34.1 (+-10.7)		36.8 (+-11.2)
Male	42 (56.0)	43 (57.3)
Female type of injury, n (%)	33 (44.0)	32 (42.7)
Ligamentous and capsular sprain	32 (42.7)	39 (52.0)
muscle strain	15 (20.0)	20 (26.7)
Contusion and bruising	14 (18.7)	4 (5.3)
Low back and lumbosacral injury	10 (13.3)	7 (9.3)
Intervertebral disk problems	4 (5.3)	5 (6.7)

Pain score at presentation, mean (+-SD) 6.21 (+-0.9) 6.0 (+-1.0)

Study protocol

We included patients older than 18 years old with acute soft tissue injury and a pain numerical rating scale score between 3 and 7. We ex- cluded patients with concurrent multitrauma or noninjury-related pain and known opioid or NSAIDs allergy; narcotics addiction (reported by either the patient or the family), history of chronic respiratory, renal, he- patic, or heart failure; patients who had received analgesics before their ED presentation; and pregnant patients and patients who were unable to understand or communicate because of language barrier or any other reason.

We used computer-generated randomization blocks of 4 to random- ly assign patients to the 2 regimen groups. First group received 10-mg oxycodone (2 oxydone, 5-mg tablet; Raha Pharmaceutical Co, Tehran, Iran), orally with water. Second group received 250-mg naproxen (Naproxen-Sobhan, 250-mg tablet; Sobhan Daroo Co, Tehran, Iran), orally with water. Patients, physicians, nurses, and research assistants

remained blinded to group assignment throughout the entire study. All study medications were prepared by a research assistant who was not involved in medication administration or data collection. We used sealed opaque envelopes to ensure allocation concealment.

We assessed pain scores (by numerical rating scale) and drugs’ ad- verse effects (including nausea, vomiting, dizziness, headache, itching, flushing, hypotension, respiratory, or central nervous system depres- sion) before, 30 minutes, and 60 minutes after medication administra- tion. A telephone follow-up was made after 24 hours to ask about the additional analgesics use and adverse effects.

Our primary outcome measure was analgesics efficacy defined as a reduction in the mean pain score by more than 2 points at 30 and 60 mi- nutes after medication administration. Our secondary outcome measure was drugs’ adverse effects.

Data analysis

Descriptive statistics are presented as mean and SD. Student t test was used to compare the means of quantitative variables in 2 indepen- dent samples. The rate of adverse effects in each group was compared with ?² test. We considered P b .05 as significant. Our study was a non- inferiority trial on continuous variable (pain score). We used the formu- la n = 2 x ([z₁-? + z₁-?]/?₀)² x S² for calculating the sample size. By considering ? = .05, ? = .20, P = .80, ?0 = 3, and S = 6, the sample size was calculated as 49 in each group. All data analyses were per- formed with SPSS, version 16 (SPSS, Inc, Chicago, IL).

Results

Basic characteristics of study patients

Baseline characteristics were similar in both groups (Table 1). Study subjects flow is illustrated as CONSORT diagram (Fig. 1).

Lost to follow-up (n = 0)

Refuse to continue participation (n = 0)

Allocated to Naproxen Group (n = 75) and Received 75 milligram naproxen

Randomized patients (n = 150)

Excluded Patients (n = 29):

-No tmeeting inclusion criteria (n = 21)

• Narcotic addiction (n = 20)
• Self-medicated with analgesics before ED arrival (n = 3)
• Pregnant (n = 1)
• Known GI disorder (n = 6)
• Known allergy to naproxen (n = 1)

- Refuse to Participate (n = 8)

Subjects Assessed for Eligibility (n = 179)

Lost to follow-up (n = 0)

Refuse to continue participation (n = 0)

Allocated to Oral Oxycodone Group (n = 75) and Received 10 milligram oxycodone

Fig. 1. CONSORT diagram showing participants flow in study.

75 Analyzed:

Excluded from analysis (n = 0)

75 Analyzed:

Excluded from analysis (n = 0)

M. Fathi et al. / American Journal of Emergency Medicine 33 (2015) 1205-1208 1207

Before any medication

6.21 +-0.9

Oxycodone

4.5+-1.4

6.0 +-1.0

Naproxen

2.6+-1.3

4.4+-1.2

Pain scale (Mean and standard deviation)

30 minutes after medication (P = .76)

60 minutes after medication (P = .45)

2.5+-1.3

Fig. 2. Pain scores before, 30 minutes, and 60 minutes after medication.

Main results

Both drugs were effective in pain control; and pain scores were sim- ilar before, 30 minutes, and 60 minutes after medication administration in both oral oxycodone and naproxen groups (Fig. 2). Twelve (16.0%) patients in oral oxycodone group and 5 (6.6%) patients in naproxen group needed more analgesics in the first 24 hours after ED discharge. This difference was not statistically significant (P = .07).

From 150 studied patients, 12 (16%) experienced nausea and 6 (8%)

experienced vomiting and Epigastric pain. Dizziness occurred in 4 (5.3%) of patients, and drowsiness and pruritis were seen in 3 (4%) and 2 (2.7%) of patients, respectively. Adverse effects were more com- mon in oral oxycodone group (P = .0001). In oral oxycodone group, nausea occurred in 10 (13.3%) patients, vomiting occurred in 6 (8.0%) patients, dizziness occurred in 4 (5.3%) patients, drowsiness occurred in 3 (4.0%) patients, and pruritis occurred in 2 (2.7%) patients. In naproxen group, only 4 (5.3%) patients experienced nausea, and no other side effect was reported. Adverse reactions are summarized in Table 2.

Discussion

Adequate soft tissue pain control is achieved by different pharmaco- logic and nonpharmacologic interventions such as using rest, ice, com- pression, and elevation [10] while avoiding heat, alcohol, re-injury, and massage [11]. There is a diverse range of analgesics to control soft tissue injury pain. NSAIDs, which are commonly used to control the soft tissue pain, inhibit the inflammatory enzymes and decrease platelet aggregation. Some investigators have suggested that this effect might lead to increased bleeding and swelling at the injury site as well as delaying the Healing process [12]. In addition, NSAIDs have substantial side effects, especially in patients with underlying health problems. Gas- trointestinal side effects (the most common side effect, seen in 10%-30%

Table 2

Rate of Adverse drug reactions in 2 studied groups

Adverse reaction	Oxycodone		Naproxen		Total
	(n = 75)		(n = 75)		(n = 150)
Nausea	10 (13.3%)		2 (2.7%)		12 (16%)
Vomiting	6 (8.0%)		0 (0.0%)		6 (8.0%)
Dizziness	4 (5.3%)		0 (0.0%)		4 (5.3%)
Drowsiness	3 (4.0%)		0 (0.0%)		3 (4.0%)
Pruritis	2 (2.7%)		0 (0.0%)		2 (2.7%)
Epigastric pain	2 (2.7%)		4 (5.3%)		6 (8%)
Total	27 (36%)		6 (8%)		33 (22%)

of patients), nephrotoxicity, bronchospasm, and thrombotic cardiovas- cular events including stroke and myocardial infarction are potential ad- verse effects of NSAIDs [13,14]. These potential side effects should alert the physicians to prescribe these medications while taking into consid- eration the patient’s comorbid condition, specific type of injury, and se- verity of pain and for the shortest duration possible [15].

Some studies promote the use of safer medications such as paracet- amol. Paracetamol has been proven to be as effective as NSAIDs (and perhaps more effective) while having no demonstrable effect on the healing process [16-18]. Oral opioids are potent analgesics for moderate-to-severe acute pain control and an important alternative for NSAIDs in patients with soft tissue injury [19,20]. The efficacy of hydrocodone/ibuprofen on ibuprofen alone and hydrocodone/ acetaminophen on acetaminophen alone has been shown in different studies [21-23]. The efficacy of single oral dose of oxycodone in compar- ison with intramuscular morphine or NSAIDs and its efficacy and safety in comparison with Intravenous morphine sulfate have also been shown in other studies [24-26].

Our study showed that both oral oxycodone and naproxen are effec- tive in soft tissue injury pain control. Although, oral oxycodone had a less favorable safety profile, as adverse effects were more common in oral oxycodone group. Our results are similar to study results of Lovell et al [27] who also showed that oral oxycodone has more adverse effects than NSAIDs (valdecoxib) in treating ED patients with acute musculo- skeletal pain. Another study on 601 patients also showed that 84% of pa- tients who used oral oxycodone to control their acute pain experienced its side effects. The use of oxycodone was associated with decreased pa- tients’ quality of life and level of activity, as drowsiness occurred in 56% of patients, dizziness occurred in 43% of patients, nausea occurred in 30% of patients, and itching occurred in approximately 27% of pa- tients [28].

Our study has some limitations. We just prescribed a single fixed dose of drugs for patients with soft tissue injury. Other studies with dif- ferent doses and enrolling patients with different causes of pain might further assess the safety and efficacy of oral oxycodone and naproxen. The exact effect of NSAIDs on healing processes is not clearly defined yet, and more complementary studies may be helpful. We included Young people in our study, and our results might not be generalized to Geriatric population. We have also studied the patients with different causes of soft tissue injury; more specific studies on subgroups with similar mechanism of injury may be beneficial.

Conclusion

Oral oxycodone is as effective as naproxen in soft tissue injury pain control but has a less favorable safety profile.

1208 M. Fathi et al. / American Journal of Emergency Medicine 33 (2015) 1205-1208

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