Topical NSAIDs for Chronic MSK pain

1. Journal Club: Topical NSAIDs
for Chronic Musculoskeletal Pain
Amanpreet Saini, MD (PGY-4)

3. Introduction
• The use of topical NSAIDs for pain relief has been a controversial
subject in analgesic practice
• Widely available in Western Europe
• In the United States (US), their use was almost unknown until 10 to
15 years ago
• In the US the Food and Drug Administration licensed topical
nonsteroidal products in 2007, and in England the National Institute
for Clinical Excellence (NICE) recommended topical therapies as first
line treatment in its guidelines for osteoarthritis in 2008 and updated
guidance in 2014

4. Reason for Study
• A systematic review of topical NSAIDs to determine the effectiveness
for relieving pain in both acute and chronic conditions
• The point of this article was to improve efficacy estimates for topical
NSAIDs, with a prior intent to determine efficacy for individual drugs

5. Methods (searching)
• Cochrane Library, MEDLINE and PreMedline, EMBASE and PubMed,
were searched for relevant studies published
• The search strategy included "application: topical" together with
"cream", "gel" etc, together with generic names of NSAIDs, and
proprietary preparations of topical treatment in which the principal
active ingredient was an NSAIDs
• Reference lists of retrieved articles were also searched
• Wrote to 20 pharmaceutical companies in the UK, 66 in continental
Europe, and two in North America, known to manufacture topical
NSAIDs, asking if they could supply papers

6. Methods (Selection)
• Identified reports of randomized, double blind, active or placebo-
controlled trials in which treatments were given to adult patients with
moderate to severe chronic pain resulting from musculoskeletal or
other painful disorders.
• EXCLUDED treatments for mouth or eye diseases
• At least ten patients had to be randomized to a treatment group and
application of treatment had to be at least once daily.
• Outcomes closest to two weeks (but at least seven days) were
extracted
• Longer outcomes were also accepted when available

7. Methods (Quality and validity assessment)
• Trial quality was assessed using a validated three-item scale with a
maximum quality score of five.
• Included studies had to score at least two points
• one for randomization
• one for blinding
• A sixteen-point scale was used to assess trial validity
• Quality and validity assessments were made independently by at least
two reviewers and verified by one other reviewer
• Disputes were settled by discussion between all reviewers.

8. Methods (Outcomes)
• Primary outcome = 50% reduction in pain at two weeks
• # of patients with a "good" or “excellent” global assessment of
treatment, or "none" or “slight” pain on rest or movement (or
comparable wording) measured on a categorical scale
• Secondary outcome:
• local adverse event (itching, stinging, rash)
• systemic adverse event

9. Methods (Quantitative data synthesis)
• The number of patients randomized into each treatment group (intention
to treat) was used in the efficacy analysis.
• Information was pooled for the number of patients in each trial
approximating at least 50% pain relief, or similar measure, for both topical
NSAID and control
• These were used to calculate NNT with a 95% confidence interval
• Relative benefit and relative risk estimates with 95% CIs were calculated
using the fixed effects model
• A statistically significant benefit of topical NSAID over control was assumed when the
lower limit of the 95% confidence interval (CI) of the relative benefit was greater
than one
• A statistically significant benefit of control over active treatment was assumed when
the upper limit of the 95% CI was less than one

10. Results
• 10 out of the 20 UK companies, and two out of the 66 continental European
companies replied to request for studies
• Only three companies supplied useful material, either published studies or bibliographies.
None provided unpublished material.
• Searches identified (60) target papers, but (35) were excluded…
• (23) studies failed to meet the inclusion criteria
• (12) had no useable data
• (25) trials therefore met the selection criteria
• (15) trials had only placebo controls
• (7) only active controls
• (3) had both placebo and active controls
• Of the (10) active controlled trials (4) compared a topical NSAID with a different topical
NSAID, (3) compared a topical NSAID with a different oral NSAID, and one each compared a
topical NSAID with a homeopathic gel, a topical rubefacient, and topical trinitroglycerin
(GTN).

11. Results
• Patients were generally over 40 years old
• Predominantly with musculoskeletal disorders
• (14) studies examined general musculoskeletal conditions
• (11) examined osteoarthritis
• Baseline pain of moderate to severe intensity

12. Placebo-controlled trials

13. Placebo-controlled trials

14. Topical Comparison

15. Discussion/Conclusion
• Patients in these trials all had moderate to severe baseline pain
• Patients with most severe disease were specifically excluded in
several trials because authors regarded topical NSAID to be
inappropriate for their treatment
• Updated review concluded that there is a body of evidence to support
the efficacy of topical NSAIDs in chronic painful musculoskeletal
conditions

16. Limitation to study
• Many trials were small, and small size can allow chance effects to
influence treatment and placebo event rates
• Different preparations were used, with different formulations,
concentrations of active ingredient, and application schedules.
• Reported outcomes were not consistent, and a hierarchy of outcomes
had to be constructed
• Possible publication bias selecting publication of trials showing topical
NSAIDs to be effective, and suppression of trials where there was no
difference between topical NSAID and placebo.

17. Disclosure
• No author has any direct stock holding in any pharmaceutical
company
• RAM & HJM have consulted for various pharmaceutical companies
• RAM, HJM & JE have received lecture fees from pharmaceutical
companies related to analgesics and other healthcare interventions
• The study was supported with Pain Research funds and by the Oxford
Pain Relief Trust.

19. Background
• Use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) to treat
chronic musculoskeletal conditions has become widely accepted
because they can provide pain relief without associated systemic
adverse events
• This review is an update of 'Topical NSAIDs for chronic
musculoskeletal pain in adults’ (2012)
• Since the last review in 2012, a number of new studies have been
published

20. Objective
• Review the evidence from randomized, double-blind, controlled trials
on the efficacy and safety of topically applied NSAIDs for chronic
musculoskeletal pain in adults

21. Search Method
• Searched the Cochrane Central Register of Controlled Trials
(CENTRAL), MEDLINE, EMBASE, in-house database (up to 2016)
• Searched the references lists of included studies and reviews, and
sought unpublished studies by asking personal contacts and searching
online clinical trial registers and manufacturers' web sites

22. Selection Criteria
• Randomized, double-blind, active or inert carrier (placebo) controlled
trials
• Treatments were administered to adults with chronic musculoskeletal
pain of moderate or severe intensity
• Had to be at least 10 participants in each treatment arm, with
application of treatment at least once daily.

23. Data Collection/Analysis
• Two review authors independently assessed studies for inclusion and
extracted data.
• Calculated risk ratio and numbers needed to treat (NNT) or harm
(NNH) compared to carrier or other active treatment
• Primary outcome was 'clinical success', defined as at least a 50%
reduction in pain, or an equivalent measure such as a 'very good' or
'excellent' global assessment of treatment, or 'none' or 'slight' pain on
rest or movement, measured on a categorical scale
• Pain relief ideally 6 to 12 weeks after treatment started

24. Results
• Identified five new studies for this update
• 10,857 participants in 39 studies, (41% increase in participants)
• 32 studies compared a topical NSAID with carrier
• All studies examined topical NSAIDs for treatment of osteoarthritis

25. Diclofenac
• Six studies (four publications; 2353 participants) of 6 to 12 weeks'
duration provided data for this outcome
• All defined 'success' as either at least a 50% reduction in pain
intensity
• The proportion of participants experiencing clinical success with
diclofenac was 60% (716/1185, range 44% to 66%)
• The proportion of participants experiencing clinical success with
carrier was 50% (582/1158, range 25% to 57%)
• The risk ratio (RR) of treatment compared with carrier was 1.2 (95%
confidence interval (CI) 1.1 to 1.3), and the NNT was 9.8 (7.1 to 16)

26. Ketoprofen
• Four studies (2573 participants) of 6 to 12 weeks' duration provided
data for this outcome
• The proportion of participants experiencing clinical success with
ketoprofen was 63% (944/1503, range 41% to 89%)
• The proportion of participants experiencing clinical success with
carrier was 48% (516/1070, range 28% to 78%).
• The RR of treatment compared with carrier was 1.1 (1.01 to 1.2), and
the NNT was 6.9 (5.4 to 9.3) (Analysis 2.1; Figure 4).
• For the 200 mg dose only (1685 participants), the RR was 1.1 (0.98 to
1.2); the NNT was not calculated.

27. Results
• In studies lasting 6 to 12 weeks, topical diclofenac and topical
ketoprofen were significantly more effective than carrier for reducing
pain
• 60% of participants had much reduced pain
• With topical diclofenac, the NNT for clinical success in six trials (2353
participants) was 9.8 (95% confidence interval (CI) 7.1 to 16) (moderate
quality evidence).
• With topical ketoprofen, the NNT for clinical success in four trials (2573
participants) was 6.9 (5.4 to 9.3) (moderate quality evidence)
• Clinical success with carrier occurred commonly - in half the
participants in studies lasting 6 to 12 weeks

28. Results
• The results of this updated review are that diclofenac gel or solution
has a modest benefit in longer-term studies of 6 to 12 weeks’
duration. The NNT of 9.8 (95% confidence interval (CI) 7.1 to 16)
barely reached statistical significance (moderate quality evidence)
• For ketoprofen gel, the NNT was 6.9 (5.4 to 9.3) (moderate quality
evidence). Barley reached statistical significance.
• NOTE: The proportion of participants reporting significant pain relief
with carrier (topical placebo) in both these analyses was about 50%
over 6 to 12 weeks

29. Limitations
• Shorter duration studies tended to be small, have less well defined
outcomes, and lack clarity on imputation methods.
• One potential bias is that some studies included clinical trials for
topical NSAIDs have not been officially published

30. Takeaway
• Topical diclofenac and topical ketoprofen can provide good levels of
pain relief in knee osteoarthritis in people aged over 40 years, but
only in about 10% more people than with carrier.