Clinical Evidence Supporting OTC Naproxen Sodium as a Nonopioid Pain Relief Option

This article was sponsored by Bayer, maker of Aleve®.

^{Aleve® temporarily reduces fever and temporarily relieves minor aches and pains due to minor pain of arthritis, muscular aches, backache, menstrual cramps, headache, toothache, and the common cold. Use as directed.}

Acute pain is a common ailment that occurs suddenly and, in many cases, has a known cause (eg, outpatient medical procedures, surgeries, and menstrual cramps). This type of pain can be multidimensional and individualized, and it typically resolves on its own.¹ Short-term use of prescription opioid medications (eg, oxycodone, hydrocodone/acetaminophen) is an option for relieving pain; however, opioid use has serious risks of misuse, addiction, and overdose-related death.²

Several studies have demonstrated that initial prescriptions of opioids for acute pain related to surgery are associated with an increased risk of chronic opioid use and misuse.^3-5 For the past 20 years, there has been an opioid crisis in the United States associated with increasing rates of opioid-related overdose death.¹ An estimated 68,000 Americans died due to an opioid overdose in 2020.⁶ Despite recent declines in total opioid prescriptions, which decreased by 44.4% between 2011 and 2020, opioid prescribing remains high across the United States.⁷

Due to the opioid crisis, several professional guidelines recommend the nonsteroidal anti-inflammatory drug (NSAID) class (prescription and OTC) as an effective initial nonopioid alternative for the management of acute pain. ^8-15

NONOPIOID OTC MANAGEMENT STRATEGIES

Acetaminophen and NSAIDs (eg, ibuprofen and naproxen sodium) are active ingredients in OTC analgesic products. These products temporarily reduce fever and relieve minor aches and pains.^16-18 The labeled dosing needed for pain relief is a key difference among these OTC options. In adults, acetaminophen 500 mg and ibuprofen 200 mg can be taken every 4 to 6 hours. Aleve^®, the leading brand of OTC naproxen sodium, can be taken every 8 to 12 hours.^16-18

Evidence generated from several clinical trials supports the use of OTC naproxen sodium as a safe and effective when used as directed option for acute pain management across various pain states (eg, dental pain, menstrual cramps, musculoskeletal pain). Pharmacists can familiarize themselves with the evidence reviewed in this article that supports the use of OTC naproxen sodium for pain.

DENTAL PAIN

The opioid combination medication hydrocodone/acetaminophen is frequently prescribed, particularly by dentists, to relieve moderate to severe pain in postoperative settings. In 2016, approximately 11.4 million opioid prescriptions were written by dentists.¹⁹ Due to opioid-related health risks, several dental associations recommend NSAIDs as first-line treatment for acute pain management.^8,9

Naproxen sodium (440 mg) vs hydrocodone plus acetaminophen (10 mg + 650 mg)

A single-center, randomized, double-blind, parallel, placebo-controlled, single-dose study evaluated the efficacy and safety of naproxen sodium versus hydrocodone plus acetaminophen for dental pain relief. Patients experiencing moderate or severe pain (N = 221) after surgical removal of impacted third molars were randomized to receive either naproxen sodium 440 mg (n = 90), hydrocodone plus acetaminophen 650 mg/10 mg (n = 87), or placebo (n = 44) over a 12-hour study period.²⁰ Naproxen sodium (440 mg) was as effective as hydrocodone plus acetaminophen in hours 0 to 4 at reducing pain intensity. It was also significantly more effective than hydrocodone plus acetaminophen in the secondary outcomes of total pain intensity (P = .01), total pain relief (0 to 6 and 0 to 12 hours, P < .05), time to rescue pain medication (P < .001), and the duration of pain at least half gone over 12 hours (P < .001).²⁰ The incidence of adverse events (AE) was higher with hydrocodone plus acetaminophen (n = 63) compared with naproxen sodium (n = 2) and placebo (n = 20).²⁰

Naproxen sodium (440 mg) vs ibuprofen (400 mg)

In a phase 3, randomized, double-blind, single-dose study, healthy individuals aged 16 to 40 years were randomly assigned to take either naproxen sodium 440 mg (n = 166), ibuprofen 400 mg (n = 165), or placebo (n = 54) over a 24-hour study period after surgical removal of third molars.²¹ Naproxen sodium provided a substantially longer duration of pain relief compared with ibuprofen and placebo (P < .001).²¹ Individuals taking naproxen sodium were 4 times more likely to have sustained pain relief over the 24-hour study period; a greater percentage of those taking naproxen sodium did not require rescue pain medications compared with individuals taking ibuprofen or placebo (65.1%, 17.0%, and 18.5%, respectively).²¹

Naproxen sodium (440 mg) vs acetaminophen (1000 mg)

In a randomized controlled, double-blind, single-dose, phase 3 study, 226 individuals with moderate to severe pain after dental extractions received either naproxen sodium 440 mg (n = 92), acetaminophen 1000 mg (n = 89), or placebo (n = 45) over a 12-hour study period.²² Naproxen sodium provided significantly greater total pain relief (based on clinical data from the first 6 hours after initial dosing) compared with acetaminophen and placebo (P < .001).²² Naproxen sodium also provided a significantly longer duration of time before repeated dosing as compared with acetaminophen and placebo (9.9 hours, 3.1 hours, and 1.1 to 2 hours, respectively; P < .001).²²

PRIMARY DYSMENORRHEA

Organizations recommend the use of NSAIDs as initial treatment for recurrent lower abdominal pain associated with menstruation, known as primary dysmenorrhea.^10,11 More than 70% of women report that they experience some degree of dysmenorrhea before or during their menstrual cycle.²³

Naproxen sodium (440 mg) vs acetaminophen (1000 mg)

A double-blind, randomized, single-dose crossover study of 201 healthy women and adolescents (aged 15-35 years) with moderate to severe primary dysmenorrhea evaluated the efficacy of naproxen sodium 440 mg compared with acetaminophen 1000 mg for 12-hour pain relief. Naproxen sodium provided significantly greater total pain relief (based on clinical data from the first 6 hours after initial dosing); further, fewer women taking naproxen sodium required rescue medications compared with those taking acetaminophen (11.2% vs 28.0% respectively; P < .01).²⁴

OSTEOARTHRITIS AND MUSCULOSKELETAL PAIN

NSAIDs are recommended by several organizations as an option for the initial management of osteoarthritis (OA) pain and musculoskeletal injuries.^12-15 A post-hoc analysis of pooled data from 4 double-blind, randomized (1:1), placebo-controlled phase 3 trials assessed analgesic efficacy and safety of naproxen sodium (440 mg/660 mg) compared with placebo over 7 days in 818 patients with moderate OA in the hip or knee.²⁵ Results from the analysis found that patients receiving naproxen sodium had significant improvements in pain relief (P < .05) and physical function (P < .05) compared with the placebo group.²⁵

ADVERSE EVENTS

A retrospective analysis of pooled safety data collected from 1494 individuals compared naproxen sodium (440 mg) with nonprescription doses of ibuprofen, acetaminophen, and placebo. Naproxen sodium (440 mg) had a similar AE rate versus placebo, and similar rates of AEs were observed across all treatment groups; dyspepsia was the most common AE experienced with naproxen sodium.²⁶

ROLE OF THE PHARMACIST

As an essential part of the health care team, pharmacists and other health care providers share a common goal of ensuring that individuals have access to nonopioid medications for effective pain relief if appropriate based on their individual medical needs. Pharmacists can identify opportunities to support the use of nonopioid medications to relieve acute pain.

If asked for a nonopioid alternative, pharmacists can discuss the growing body of evidence that supports the use of an NSAID as a first-line OTC option for acute pain. If asked for a specific product recommendation, pharmacists can share that Aleve^® is a safe, long-acting nonopioid option that is effective when used as directed for the temporary relief of minor aches and pains due to headache, backache, toothache, menstrual cramps, muscular aches, and arthritis pain.¹⁶

REFERENCES

1. U.S. Department of Health & Human Services. Pain management best practices inter-agency task force report. Published May 6, 2019. Accessed May 19, 2022. https://www.hhs.gov/sites/default/files/pain-mgmt-best-practices-draft-final-report-05062019.pdf

2. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain - United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49. doi:10.15585/mmwr.rr6501e1. Published correction appears in MMWR Recomm Rep. 2016;65(11):295.

3. Brummett CM, Waljee JF, Goesling J, et al. New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg. 2017;152(6):e170504. doi:10.1001/jamasurg.2017.0504

4. Schroeder AR, Dehghan M, Newman TB, Bentley JP, Park KT. Association of opioid prescriptions from dental clinicians for US adolescents and young adults with subsequent opioid use and abuse. JAMA Intern Med. 2019;179(2):145-152. doi:10.1001/jamainternmed.2018.5419

5. Sun EC, Darnall BD, Baker LC, Mackey S. Incidence of and risk factors for chronic opioid use among opioid-naive patients in the postoperative period. JAMA Intern Med. 2016;176(9):1286-1293. doi:10.1001/jamainternmed.2016.3298

6. Overdose death rates. National Institute on Drug Abuse. January 28, 2022. Accessed June 8, 2022. https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates

7. 2021 AMA overdose epidemic report. American Medical Association. September 2021. Accessed May 17, 2022. https://end-overdose-epidemic.org/wp-content/uploads/2021/09/AMA-2021-Overdose-Epidemic-Report_92021.pdf

8. Opioid prescribing: acute and postoperative pain management. American Association of Oral and Maxillofacial Surgeons. 2020. Accessed May 16, 2022. https://www.aaoms.org/docs/govt_affairs/advocacy_white_papers/opioid_prescribing.pdf

9. Statement on the use of opioids in the treatment of dental pain. American Dental Association. October 2016. Accessed June 8, 2022. https://www.ada.org/about/governance/current-policies#substanceusedisorders

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16. Aleve professional information. Bayer HealthCare. 2021. Accessed May 17, 2022. https://www.bayer.com/sites/default/files/Aleve%20Professional%20Information%202021.pdf

17. Advil (ibuprofen tablet). Drug label. National Institutes of Health DailyMed. April 2022. Accessed June 8, 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=772360bd-8631-4d24-b4db-5a7e6e1d9a13

18. Tylenol (acetaminophen tablet) Drug Label. National Institutes of Health DailyMed website. May 2020. Accessed June 8, 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1622f694-4d63-4c56-8737-fae31f0ecfb7

19. Suda KJ, Durkin MJ, Calip GS, et al. Comparison of opioid prescribing by dentists in the United States and England. JAMA Netw Open. 2019;2(5):e194303. doi:10.1001/jamanetworkopen.2019.4303

20. Cooper SA, Desjardins PJ, Bertoch T, et al. Analgesic efficacy of naproxen sodium versus hydrocodone/acetaminophen in acute postsurgical dental pain: a randomized, double-blind, placebo-controlled trial. Postgrad Med. 2021;1-8. doi:10.1080/00325481.2021.2008180

21. Cooper SA, Desjardins P, Brain P, et al. Longer analgesic effect with naproxen sodium than ibuprofen in post-surgical dental pain: a randomized, double-blind, placebo-controlled, single-dose trial. Curr Med Res Opin. 2019;35(12):2149-2158. doi:10.1080/03007995.2019.1655257

22. Kiersch TA, Halladay SC, Hormel PC. A single-dose, double-blind comparison of naproxen sodium, acetaminophen, and placebo in postoperative dental pain. Clin Ther. 1994;16(3):394-404.

23. Armour M, Parry K, Manohar N, et al. The prevalence and academic impact of dysmenorrhea in 21,573 young women: a systematic review and meta-analysis. J Womens Health (Larchmt). 2019;28(8):1161-1171. doi:10.1089/jwh.2018.7615

24. Daniels SE, Paredes-Diaz A, An R, Centofanti R, Tajaddini A. Significant, long-lasting pain relief in primary dysmenorrhea with low-dose naproxen sodium compared with acetaminophen: a double-blind, randomized, single-dose, crossover study. Curr Med Res Opin. 2019;35(12):2139-2147. doi:101080/03007995.2019.1654987

25. Couto A, Troullos E, Moon J, Paredes-Diaz A, An R. Analgesic efficacy and safety of non-prescription doses of naproxen sodium in the management of moderate osteoarthritis of the knee or hip. Curr Med Res Opin. 2018;34(10):1747-1753. doi:10.1080/03007995.2018.1437029

26. Kyeremateng K, Troullos E, Paredes-Diaz A. Safety of naproxen compared with placebo, ibuprofen and acetaminophen: a pooled analysis of eight multiple-dose, short-term, randomized controlled studies. Curr Med Res Opin. 2019;35(10):1671-1676. doi:10.1080/03007995.2019.1612338