This presentation is regarding naproxen.

1. Naproxen
RA , OA, Spondylitis, Post operative and
Musculoskeletal injuries
1

2. Classification
of NSAIDs
(Nonsteroidal
anti-
inflammatory
drugs)

3. What is
COX1 and
COX2 ?
Naproxen
Naproxen

4. 4

5. Pharmacodynami
c
It has anti-inflammatory
,analgesic and antipyretic
action

6. Cardiac Safe
NSAID

7. Lancet 2013; 382: 769–79
Coxib and Diclofenac: Increased Major Vascular Events
Ibuprofen: Increased major coronary events
Naproxen: Less vascular risk than other NSAIDs
Meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 person years) and 474 trials of one
NSAID versus another NSAID (229 296 participants, 165 456 person-years)
Coxib and Diclofenac
Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14–1·66; p=0·0009) or
diclofenac (1·41, 1·12–1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31–2·37;
p=0·0001; diclofenac 1·70, 1·19–2·41; p=0·0032)
Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00–2·49; p=0·0103) and diclofenac (1·65, 0·95–2·85,
p=0·0187)
Ibuprofen
Significantly increased major coronary events (2·22, 1·10–4·48; p=0·0253)
Naproxen
Did not significantly increase major vascular events (0·93, 0·69–1·27)
Vascular death was not increased by naproxen (1·08, 0·48–2·47, p=0·80)
High-dose naproxen is associated with less vascular risk than other NSAIDs

8. 8
BMJ 2011; 342 (Published 11 January 2011)
Naproxen seems to be the safest analgesic for patients with
osteoarthritis in cardiovascular terms
Among the seven NSAIDs analysed, naproxen seemed least harmful
for cardiovascular safety
•31 trials in 116 429 patients with more than 115 000 patient
• Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility
interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21).
•Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36)
• Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of
cardiovascular death
•Naproxen seems to be the safest analgesic for patients with osteoarthritis in cardiovascular terms
•Among the seven NSAIDs analysed, naproxen seemed least harmful for cardiovascular safety

9. Pharmacokinetic
s
9
T1/2
Naproxen 12–17 hours.
Diclofenac 1–2 hours
Aceclofenac 4 hours
Ibuprofen 1.8–2.4 hours
Mefenamic acid 2 hours
Nimesulide 1.96 to 4.73 hours
Aspirin 15–20 minutes
Paracetamol 1.25–3 hours.
Etodolac 6.4-8.4 hours
Flurbiprofen 3.8 hours
Ketoprofen 1.8 hours
Fenoprofen 2.5 hours
Indomethacin 4-5 hours
Meloxicam 20 hours
Piroxicam 57 hours
Adopted from Rx information

10. Pharmacokinetics
10
Pharmacokinetics
Naproxen Naproxen sodium Reference
Bioavailability 95% 95% US FDA
approved
prescription
information.
Peak plasma
concentration
2–4 hours 1–2 hours
Onset of action 1 hr 30 mins (US FDA
monograph), naproxen
sodium begins to work
within 15 minutes
[Br.J. Clin. Pharmac.
(1980), 10, 259-263].
Duration of
action
12 hrs 12 hrs US FDA
approved
prescription
information.
Protein binding >99% >99%
Metabolism Liver Liver
Excretion Urine (95%) Urine (95%)
Half life 12-17 hrs 12-17 hrs

11. Indications
•US FDA approved prescription information
11
Naproxen Naproxen sodium
Inflammatory Diseases
Osteoarthritis, Rheumatoid
Arthritis, or Ankylosing Spondylitis
Osteoarthritis, Rheumatoid Arthritis, or Ankylosing
Spondylitis
Acute conditions Acute Tendinitis/Bursitis, Gout,
dysmenorrhea
Acute Tendinitis/Bursitis, Gout, dysmenorrhea
Headache / Migraine Not preferred Preferred
Fever Not approved Approved as OTC
Recommendation Naproxen sodium is preferred for management of
acute painful conditions when prompt onset of pain
relief is desired
OTC Not approved (USA) Approved (USA) for fever and pain

12. Clinical overview
Focus of Fever , Headache , Body ach Associated with
Respiratory Infections
12

13. Naproxen in the management of
osteoarthritis
European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis
(ESCEO) treatment algorithm recommends
Naproxen preferable to diclofenac, the Naproxen being associated with lower CV risk
Naproxen may be the preferred agent in osteoarthritis patients at high CV risk
13
Semin Arthritis Rheum. 2016 Feb;45(4 Suppl): S22-7.

14. Osteoarthritis
• 723 studies of all
conservative therapies
• Naproxen ranked most
effective among conservative
treatments of KOA because
of its relative safety and low
cost
14
J Am Acad Orthop Surg. 2018 May 1;26(9):325-336.

15. Mixed Treatment Comparisons for Nonsurgical Treatment of Knee
Osteoarthritis: A Network
Meta-analysis of 56 studies analysed
Cumulative probabilities showed naproxen to be the most effective
individual treatment
Naproxen ranked most effective among conservative treatments of
Knee OA
Should be considered when treating pain and function because of its
relative safety and low cost
15

16. 16
J Am Acad Orthop Surg. 2018 May 1;26(9):325-336.

17. 17
Effect of nonsteroidal anti-inflammatory drugs on the C-reactive protein
level in rheumatoid arthritis: a meta-analysis of randomized controlled
trials
19 trials of 10 different NSAIDs
NSAIDs showed no effect on the CRP level (SMD 0.01 [95% CI -0.03, 0.06], P = 0.62)
Naproxen caused a statistically significant and consistent (I(2) = 0%) decrease in the CRP level (SMD -0.11
[95% CI -0.20, -0.02], P = 0.022)
Nonselective NSAID naproxen was associated with a significant decrease in the CRP level, whereas the
cyclooxygenase 2-selective NSAID lumiracoxib was associated with a significant increase in the CRP level.
This finding is interesting considering the suspected influence of NSAIDs on cardiovascular complications.
Simon Tarp et al., Arthritis Rheum. 2012 Nov;64(11):3511-21

18. A systematic review and meta-analysis of naproxen for
prevention heterotopic ossification after hip surgery
4 studies including 269 patients
Compared with control group, administration naproxen was associated with a significantly reduction of the
occurrence of HO at final follow-up after hip surgery (P < .05)
Naproxen was associated with a reduction of the Brooker I and II HO (P < .05)
No significant difference between the Brooker III HO between naproxen and control groups (P > .05)
No significant difference between the complications (P > .05) between naproxen and control groups.
Naproxen has a beneficial role in reducing the total occurrence of HO, Brooker I and II HO after hip surgery.
18
Ai-Hua Zhang et al., Medicine (Baltimore) . 2019 Apr;98(14):e14607.

19. Naproxen in Knee Osteoarthritis
Clinical Studies
19

20. Mixed Treatment Comparisons for Nonsurgical Treatment of Knee
Osteoarthritis: A Network Meta-analysis
• Meta-analysis
Study Design
• Data from PubMed, EMBASE, and Cochrane Central
Register of Controlled Trials (CENTRAL
Study Population
• 2956 articles, 79 RCTs examining KOA treatments
met all inclusion criteria for the NMA
Sample size
• In comparison to other conservative KOA therapies, this
study supports the use of naproxen sodium, which is low
cost and has a favourable cardiac risk profile.
• It also reveals that naproxen is the most effective
sole treatment for improving pain and function.
Results 1 :
• Function: Neither of the two oral placebos nor any IA
therapies demonstrated clinical relevance, and naproxen
was the only medication to do so.
Results 2 :
• NMA supports naproxen as the conservative treatment of
choice, as it is most probable to improve pain and
function in patients with symptomatic KOA, followed by
an IA corticosteroid, IA PRP, celecoxib, and ibuprofen
Results 3:
Conclusions: Naproxen ranked most effective among conservative treatments of KOA and should be considered
when treating pain and function because of its relative safety and low cost
J Am Acad Orthop Surg. 2018 May 1;26(9):325-336.
1

21. The five treatments with the highest
probability of ranking 1 to 5 (1
being most effective) when
evaluating pain reduction are IA
corticosteroids, ibuprofen, IA PRP,
naproxen, and celecoxib (Figure 3)
21
J Am Acad Orthop Surg. 2018 May 1;26(9):325-336.

22. Analgesic efficacy and safety of non-prescription doses of naproxen sodium in
the management of moderate osteoarthritis of the knee or hip
• Multi-center, multi-dose, randomized, parallel, double-
blind, placebo-controlled studies
Study Design
• Oral naproxen sodium (age-based dosing regimen:
<65 years, 660 mg/day; ≥65 years, 440 mg/day)
Study Population
• 818 patients
Sample size
• Naproxen sodium or placebo (n = 409 in each group)
Study group
• 7 day
Study duration
• Significant improvements in pain and physical function
with naproxen sodium (p < .05)
• Treatment was rated "good" to "excellent" significantly
more often (p < .001) by investigators and patients
Results 1 :
• No significant differences in adverse events between
groups, regardless of age.
Results 2 :
• Pooled analysis demonstrates that non-prescription
doses of naproxen sodium (440/660 mg per day)
effectively relieve pain in patients with moderate OA of
the hip or knee.
Results 3:
Conclusions: Non-prescription naproxen sodium is effective and well tolerated in patients of all ages for the
acute therapy of underlying pain in patients with moderate osteoarthritis of the hip or knee.
Curr Med Res Opin. 2018 Oct;34(10):1747-1753.
2

23. • 2 identical Multicenter, randomized, double-blind, placebo-controlled, multidose,
parallel-design studies,
• Patients aged > or = 25 years with OA were randomized to daily doses of naproxen
sodium 660 mg, naproxen sodium 440 mg (patients > or = 65 years), ibuprofen 1200
mg, or placebo, for 7 days.
• Naproxen sodium (440/660 mg) significantly improved all 7 symptoms from baseline
compared with placebo.
• Naproxen sodium (440/660 mg) and ibuprofen (1200 mg) effectively relieve pain in
patients with mild to moderate OA of the knee.
• Naproxen sodium provided more effective pain relief for most variables compared with
placebo, and for night pain compared with ibuprofen.
• Efficacy was combined with good safety and tolerability.
J Rheumatol. 2004 Jul;31(7):1373-83.
3

24. • For each of the different symptoms,
naproxen sodium (440/660 mg) was
significantly superior to placebo at
improving symptoms from baseline (Figure
2A)
• Subgroup of elderly patients, sodium 440
mg was significantly superior to placebo in
all symptoms apart from pain on weight-
bearing.
• Although improvement in this symptom did
not reach statistical significance (p =
0.064),there was greater improvement
following treatment with naproxen
sodium compared with placebo and
ibuprofen.
J Rheumatol. 2004 Jul;31(7):1373-83..

25. • 25 patients with knee OA received naproxen (500 mg), placebo, or no treatment in 3
separate sessions in a randomized manner
• Naproxen effectively reduces pain-related brain responses involving
different regions and the attenuation is related to subjective pain
changes.
The Journal of Rheumatology November 2014, 41 (11) 2240-2248.
4

26. Naproxen for the treatment of
gout arthritis
Clinical Studies
26

27. Open-label randomised pragmatic trial (CONTACT) comparing naproxen and
low-dose colchicine for the treatment of gout flares in primary care
• Randomized, multicenter, open-label, pragmatic
clinical trial
Study Design
• Aged 18 years and over, consulting for a current gout
flare
Study Population
• 399 participants (naproxen n=200, colchicine n=199)
Sample size
• Single initial dose of oral naproxen 750 mg (three 250
mg tablets) followed by 250 mg (one tablet) every 8
hours for up to 7 days
• Oral colchicine 500 mcg (one tablet) every 8 hours for
4 days
Study group
• Treatment was continued until the affected joint was
pain-free.
Study duration
Conclusions:Naproxen was associated with fewer side effects, less analgesic use and slightly lower costs,
suggesting that, in the absence of contraindications, naproxen should be used ahead of low-dose colchicine to
treat gout flares in primary care.
Roddy E, et al. Ann Rheum Dis 2020;79:276–284.
• There was no difference between the effect of naproxen
and low-dose colchicine on pain from.
Results 1 :
• Naproxen was associated with fewer side effects, lower
use of other analgesics and was cost-effective.
Results 2 :
• No difference in pain intensity over 7 days between
people with a gout flare randomised to either naproxen or
low-dose colchicine. Naproxen caused fewer side effects
supporting naproxen as first-line treatment for gout flares
in primary care in the absence of contraindications
Results 3:
1

28. Multicentre trial of naproxen and phenylbutazone in acute gout
• open design trial
Study Design
• 41 patients with acute gout
Study Population
• Naproxen (n= 22 patients), Phenylbutazone (n=23), 4
patients receiving both drugs in different attacks
Sample size
• Naproxen 750 mg as a single dose followed by 250
mg three times daily
• Phenylbutazone 200 mg four times daily for 48 hours
followed by 200 mg three times daily
Study group
• Treatment was continued until the affected joint was
pain-free.
Study duration
• Phenylbutazone-treated patients were found to be
younger than the naproxen group (P=003) and duration
of attack before starting treatment was significantly
shorter (P=003) in the phenylbutazone group (mean< 1
day) than in the naproxen group (mean 2 days)
Results 1 :
• Naproxen is equally as effective as phenylbutazone in
the treatment of acute gout, the success rate (87 %
phenylbutazone, 83 % naproxen)
Results 2 :
• Naproxen is a safe and effective addition to the small
group of drugs in current use for the treatment of acute
gout.
Results 3:
Conclusions: Both the drugs were equally effective with few and relatively mild side effects.
Naproxen is a useful alternative agent for the treatment of acute gout.
Annals of the Rheumatic Diseases, 1977, 36, 80-82
2

29. The Treatment of Acute Gout with Naproxen
• Open study
Study Design
• 17 men and 3 women varying in age from 35 to 89
years.
Study Population
• 20 patients with acute gout
Sample size
• 12 patients received an initial dose of 600 mg
followed by 300 mg at 8-hour intervals.
• 8 patients were treated with 750 mg naproxen initially,
followed in 8 hours with 500 mg and thereafter with
250 mg at 8-hourly intervals for 48 to 72 hours.
Study group
• 72 hours
Study duration
• No serious side effects of naproxen or significant
deviations from baseline in laboratory tests were
encountered during the study.
Results 1 :
• 15 of the 20 patients with acute gout responded
favorably to naproxen therapy
Results 2 :
• Pain and tenderness showed a comparable decline
irrespective of the loading dose of naproxen.
• 8 patients treated with the higher loading dose showed a
greater decline in swelling at 48 hours
Results 3:
Conclusions: Naproxen, a new anti-inflammatory phenylalkanoic acid given in total doses of 2.4 to 4.5 Gm, was
effective in the treatment of acute gout. No gastrointestinal or serious side effects were encountered.
Scand J Rheumatol Suppl. 1973;2:69-71.
3

30. Table 1: Time of Entry into Study After Onset of Attack of Acute Gout and Results After
Naproxen Treatment for the 20 Patients Studied
• 15 of the 20 patients with acute gout responded favorably to naproxen therapy
(Table I)
Scand J Rheumatol Suppl. 1973;2:69-71.

31. Acute dental pain
• 12 studies, 587 participants
• Naproxen sodium shows a
stronger analgesic effect
either at 2 h or 6 h, and its
effect lasts to 24 h.
31
BMC Oral Health. 2020 Sep 18;20(1):259.

32. OTC
safety
• 46 clinical trial (Dental pain, Cold, Arthritis, Dysmenorrhea,
Headache, Fever, Myalgia)
• Treatment with naproxen sodium may be highly beneficial from a
clinical and economical perspective and safe when adhering to
labeled directions.
32
J Clin Pharmacol. 2001 Feb;41(2):127-38.

33. Naproxen in
Post operative
pain and
inflammation
Clinical Overview

34. Post -Op
pain
• 10 studies with 996
participants
• Provided effective
analgesia to adults with
moderate to severe acute
postoperative pain
34
Cochrane Database Syst Rev. 2009 Jan 21;2009(1):CD004234

35. Longer analgesic effect with naproxen sodium than ibuprofen in post-
surgical dental pain: a randomized, double-blind, placebo-controlled,
single-dose trial
35
n = 385; mean age = 19 years
time to rescue medication was significantly (p < .001) longer with NAPSO than IBU and
placebo.
Fewer NAPSO subjects required rescue medication (58/166, 34.9%) compared with IBU
(137/15, 83.0%) and placebo (44/54, 81.5%).
Duration of pain relief after a single dose of NAPSO was significantly longer than after IBU, and
significantly fewer NAPSO-treated subjects required rescue medication over a 24-h period.
Curr Med Res Opin. 2019 Dec;35(12):2149-2158

36. Comparison of the postoperative analgesic effects of
naproxen sodium and naproxen sodium-codeine phosphate
for arthroscopic meniscus surgery
36
Median VAS scores both at rest and on movement were significantly lower in Group
NC compared with Group N, except 18(th) hour on movement (p<0.05)
The median time to the first demand of PCA was shorter in Group N compared with
Group NC (p<0.001).
Meperidine consumption was higher in Group N compared with Group NC (p<0.001).
There was no difference between groups with respect to side effects (p>0.05).
The combination of naproxen sodium-codeine phosphate provided more effective
analgesia than naproxen sodium and did not increase side effects.
Braz J Anesthesiol. 2016 Mar-Apr;66(2):151-6.

37. Oral naproxen but not oral paracetamol reduces the need for
rescue analgesic after adenoidectomy in children
37
When pethidine was not used, 83% of the children in the naproxen group vs. 97% in the other
two groups required rescue fentanyl (P < 0.05).
The use of pethidine reduced the incidence of fentanyl requirement by 30% and the number of
fentanyl doses by 50% (P < 0.001).
It also equalized the effects of naproxen, paracetamol and the placebo making the pain model
invalid for this kind of study.
Oral naproxen (10 mg/kg), but not oral paracetamol (20 mg/kg), reduces the need for rescue
analgesic after adenoidectomy in children. The sensitivity of the pain model is crucial for these
types of studies.
Acta Anaesthesiol Scand. 2007 Jul;51(6):726-30.

38. Ranked No. 1
Longest acting NSAID (15 hrs)
Cardiac safe NSAID
Textbook product
Thank you
38