Drugs, Health Technologies, Health Systems
Summary
Main Take-Aways
Topical diclofenac appears to be an effective, well-tolerated option for osteoarthritis and acute or chronic musculoskeletal pain, with fewer stomach side effects than oral diclofenac.
For topical ketamine, baclofen, clonidine, gabapentin, ketoprofen, and nifedipine, the evidence is generally limited, mixed, or low quality. Although some of these drugs may show benefits for pain associated with specific conditions, such as nifedipine for anal fissures or pressure ulcers and diclofenac for cancer pain and for prevention of capecitabine-associated hand-foot syndrome, more high-quality research is needed before they can be routinely recommended.
Key Messages
What Is the Issue?
Topical use of drugs for pain management has been gaining interest, given that it may limit the systemic adverse events (AEs) associated with oral drugs for the treatment of pain management, without losing analgesic efficacy.
Decision-makers are interested in understanding whether topical drugs such as amitriptyline, baclofen, clonidine, diclofenac, gabapentin, ketamine, ketoprofen, and nifedipine could be used for the treatment of chronic or acute pain associated with various conditions such as osteoarthritis, musculoskeletal system conditions, neuropathy, anal fissures, vulvodynia, pressure ulcers, and cancer.
Decision-makers are also interested in the efficacy of these compounds in different formulations, at different concentrations, or in combination with each other or with other compounds.
What Did We Do?
We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence published since 2016. We expanded the search for topical nifedipine and gabapentin to relevant evidence published since 2010, given that limited relevant evidence was found in the first search period.
What Did We Find?
We included 36 publications, comprising 7 systematic reviews and 29 randomized controlled trials evaluating the clinical efficacy and safety of 7 topical drugs (i.e., ketamine, ketoprofen, baclofen, clonidine, nifedipine, gabapentin, and diclofenac) for the treatment of pain associated with various clinical conditions. We did not find any relevant evidence for amitriptyline. We found evidence for the use of topical medications for the conditions of interest, as described in the following bullets.
Findings for osteoarthritis:
Topical ketoprofen in transferosome gel showed little to no difference in pain relief and improvement in physical function, no difference in systemic AEs, and increases in local AEs (e.g., skin and soft tissue disorders) in adults, compared to placebo.
Topical diclofenac of different formulations, carriers, and concentrations appeared to be more effective than placebo for pain relief and improvement in physical function and stiffness in adults. The benefits of topical diclofenac appeared to be dose-dependent, with minimal AEs. Both topical and oral formulations of diclofenac appeared to provide similar levels of pain relief, with more local AEs (i.e., skin disorders) associated with topical diclofenac, whereas more systemic AEs (i.e., gastrointestinal [GI] disorders) were associated with oral diclofenac.
Findings for chronic musculoskeletal pain:
Topical diclofenac patches of different concentrations were equally effective for the control of low back pain in adults compared to placebo. Topical diclofenac patches may be as effective as oral diclofenac sustained-release tablets in the treatment of adults with chronic musculoskeletal pain, but they cause fewer GI side effects.
Findings for neuropathic pain:
We did not find any clear evidence that topical ketamine reduced pain intensity at the immediate- or short-term follow-up in adults with neuropathic pain compared to placebo.
The evidence was inconclusive regarding whether topical baclofen reduced neuropathic pain intensity in adults during short-term treatment compared to placebo.
There was no evidence that topical clonidine was better than placebo for improvement of neuropathic pain in adults.
Findings for anal fissures:
Topical nifedipine may result in better pain relief and may achieve a better rate of ulcer healing compared to conservative treatment in adults. There was no evidence of a difference between topical nifedipine and oral nifedipine tablets for pain relief or ulcer healing.
Findings for vulvodynia:
Topical gabapentin treatment of vulvodynia may result in pain relief based on before-after studies. However, conclusions cannot be made due to methodological heterogeneity and inherent limitations of the studies.
We found no difference in the effectiveness of topical nifedipine compared to placebo for the treatment of vulvodynia in adults.
Findings for pressure ulcers:
Topical nifedipine may improve the healing process of stage 1 or 2 pressure ulcers in critically ill adult patients.
Findings for acute musculoskeletal pain:
Topical ketoprofen gel was superior to placebo in the immediate reduction in pain intensity from ankle sprain in children and adults in an emergency setting. However, the effectiveness of topical ketoprofen in transferosome gel did not exceed that of the transferosome carrier alone.
Topical diclofenac of different concentrations and formulations was effective for acute musculoskeletal pain in adolescents and adults compared to placebo, with minimal AEs. It was inconclusive whether the effect of topical diclofenac is dose-dependent.
Findings for cancer-related pain or conditions:
Topical clonidine mucobuccal tablets at either concentration (50 mcg or 100 mcg) may result in little to no difference compared to placebo for the prevention of severe oral mucositis in patients who underwent chemoradiation for the treatment of head and neck cancer.
Topical diclofenac gel application was associated with a lower rate of capecitabine-associated hand-foot syndrome in patients with breast and GI cancer, a lower rate of capecitabine dose reduction, and a better quality of life compared to placebo.
In the treatment of cancer pain, topical diclofenac patches may result in a longer analgesic effect compared to placebo, and better improvement in pain relief, sleep quality, and patient satisfaction.
What Does It Mean?
Topical diclofenac appears to be an effective, well-tolerated option for osteoarthritis and acute or chronic musculoskeletal pain, with fewer stomach side effects than oral diclofenac.
For topical ketamine, baclofen, clonidine, gabapentin, ketoprofen, and nifedipine, the evidence is generally limited, mixed, or low quality. Although some of these drugs may show benefits for pain associated with specific conditions, such as nifedipine for anal fissures or pressure ulcers and diclofenac for cancer pain and for prevention of capecitabine-associated hand-foot syndrome, more high-quality research is needed before they can be routinely recommended.
AE
adverse event
AMSTAR 2
A MeaSurement Tool to Assess systematic Reviews 2
CGI-I
Clinical Global Impressions–Improvement
DN4
Douleur Neuropathique en 4 Questions
GI
gastrointestinal
HFS
hand-foot syndrome
HTA
health technology assessment
MID
minimal important difference
NMDA
N-methyl-d-aspartate
NRS
numerical rating scale
NSAID
nonsteroidal anti-inflammatory drug
OMDQ
Oral Mucositis Daily Questionnaire
PGA
patient global assessment
PGIC
Patient Global Impression of Change scale
QoL
quality of life
RCT
randomized controlled trial
RMDQ
Roland-Morris Disability Questionnaire
RoB 1
original Cochrane risk-of-bias tool for randomized trials
RoB 2
revised Cochrane risk-of-bias tool for randomized trials
SR
systematic review
VAS
visual analogue scale
WOMAC
Western Ontario and McMaster Universities Osteoarthritis Index
Pain is an unpleasant sensory and emotional experience that is highly personal.1 Pain can be mild or severe in intensity, and may include pricking, tingling, stinging, burning, shooting, aching, or electric sensations.1 Pain is commonly classified by acute or chronic duration.
Acute pain is defined as pain lasting less than 3 months in duration.1 It is associated with musculoskeletal injuries resulting from sports injuries and soft tissue injuries such as muscle soreness or cramps.1 Acute pain starts suddenly and ends when the cause of pain is treated. In some cases, acute pain might persist and become chronic pain.1
Chronic pain is defined as pain lasting 3 months or more, or pain caused by a particular condition for which the expected healing time is longer than 3 months.1 Common types of chronic pain include osteoarthritis, lower back pain, fibromyalgia, migraine headaches, and neuropathic (nerve) pain.2 Cancer pain can be both acute and chronic, depending on the stage of the disease, the specific cause, and whether active treatment is sought.3
The goal of pain management is to relieve pain as much as possible, improve physical function, and enhance quality of life.1 Treatment options may vary depending on the type of pain and its duration. They include medications and substances (e.g., opioids, cannabinoids), medical procedures and devices, behavioural medicine and physical therapy, and lifestyle changes.1
Common pain medications include analgesics like acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen and diclofenac, and prescribed opioids.1 Antiseizure, antidepressant, and antihypertensive medications such as gabapentin, ketamine, amitriptyline, and clonidine can also help relieve pain and may be most effective for neuropathic pain.1 Muscle relaxants such as baclofen and nifedipine are prescribed to reduce tension in muscles and can help manage musculoskeletal pain.1 Some topical gel, cream, or patch formulations of these medications are available to provide fast, targeted relief for localized pain management while minimizing systemic AEs.4
Brief descriptions of each of the medications included in this review are presented as follows:
Baclofen is a gamma-aminobutyric acid agonist that acts on the nerves in the spinal cord to stop muscles from overcontracting (causing muscle stiffness, cramping, and spasms) as a result of conditions like multiple sclerosis, spinal cord injury, or other neurologic conditions.5
Clonidine alters how the body processes pain signals by binding to alpha-2 receptors in the dorsal horn of the spinal cord, thereby effectively blocking pain signals from travelling up to the brain.6 Because clonidine also exhibits anti-inflammatory activities, it may reduce local inflammation caused by chemoradiation in patients with cancer.7
Diclofenac is a widely used NSAID to treat mild-to-moderate pain and reduce inflammation, swelling, and joint stiffness.8 Topical diclofenac can be applied directly to the skin and is used to relieve joint and muscle pain.
Gabapentin is an anticonvulsant primarily used to treat chronic nerve pain (neuropathic pain).9 It is also used off-label to treat persistent nerve pain in patients with vulvodynia.
Ketamine is primarily a dissociative anesthetic and is used at high doses in operating rooms and emergency departments.10 Because it is a noncompetitive antagonist for N-methyl-d-aspartate (NMDA) receptors, it is used at subanesthetic doses that modulate NMDA receptors and downstream glutamatergic signalling in the brain and spinal cord, interrupting the chronic pain loop and reducing central sensitization for pain.10,11
Ketoprofen is an NSAID that inhibits cyclooxygenase-1 and –2, enzymes involved in pain, and it is used to relieve pain, swelling, and fever.12
Nifedipine is a calcium channel blocker and vasodilator that prevents calcium from entering the muscle cells of the heart and blood vessels, relaxing the arteries and smooth muscles.13 For anal fissures, topical nifedipine is frequently used to relax the sphincter muscle, reducing severe pain and allowing tears to heal. Topical nifedipine is sometimes prescribed off-label for vulvodynia (chronic vulvar pain) to relieve hypertonic pelvic muscles and improve blood flow. By acting as a calcium channel blocker, nifedipine promotes vasodilation and improves local blood flow to the compromised skin tissue, accelerating the healing of pressure ulcers.
Long-term use of oral or IV medications for pain management may increase the risk of GI irritation, ulcers, cardiovascular events, and kidney damage.14 Consequently, there is increasing demand for and attention to nonsystemic topical medications for pain management.
Topical analgesics are generally recommended before oral analgesics for pain management due to their lower systemic absorption, which results in a better safety profile.4 The benefits of topical drugs include the ability to block or inhibit local or peripheral pain pathways, provide fast and targeted pain relief, avoid systemic AEs and GI distress, minimize drug-to-drug interactions, and provide an excellent alternative option for children or older adults who have trouble swallowing pills.4 Topical medications can accumulate at therapeutic concentrations within the local tissue while maintaining low plasma concentration. Therefore, they potentially have similar effects compared to oral medications without the systemic AEs associated with oral medications.15
This review was undertaken to evaluate the efficacy and safety of various topical analgesics (i.e., ketamine, amitriptyline, ketoprofen, baclofen, clonidine, nifedipine, gabapentin and diclofenac) for pain management in different conditions.
What is the clinical efficacy and safety of topical ketamine, amitriptyline, ketoprofen, baclofen, clonidine, nifedipine, gabapentin, and diclofenac for pain management?
What is the comparative clinical efficacy and safety of topical formulations versus oral and injectable formulations of ketamine, amitriptyline, ketoprofen, baclofen, clonidine, nifedipine, gabapentin, and diclofenac for pain management?
What is the clinical efficacy and safety of topical ketamine, amitriptyline, ketoprofen, baclofen, clonidine, nifedipine, gabapentin, and diclofenac for pain management at different concentrations, in combination with each other, or in combination with other compounds?
An information specialist conducted a literature search on key resources including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of health technology assessment agencies (HTA) in Canada and major international HTA agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevance. The search strategy comprised both controlled vocabulary, such as the US National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were ketamine, amitriptyline, ketoprofen, baclofen, clonidine, diclofenac, and topical administration. Search filters were applied to limit retrieval to HTAs, systematic reviews (SRs), meta-analyses, or indirect treatment comparisons, randomized controlled trials (RCTs), controlled clinical trials, and any other type of clinical trial. The search was completed on April 14, 2026, and limited to English-language documents published since January 1, 2016. An expanded search was conducted for nifedipine, gabapentin, and topical administration to capture English-language documents published since January 1, 2010. The search strategies are available on request.
The screening occurred in 2 steps; first, we screened by titles and abstracts, then by full text. Two reviewers participated in a pilot exercise using the same 50 abstracts to calibrate and validate the screening process. We reached an agreement of 96% and resolved discrepancies through discussion. Thereafter, a single reviewer screened the remaining abstracts.
The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Criteria | Description |
|---|---|
Population | Adult and pediatric patients requiring pain management for osteoarthritis, musculoskeletal (chronic or acute), neuropathy, anal fissures, vulvodynia, pressure ulcers, and cancer-related conditions |
Priority populations of interest (if relevant) |
|
Intervention | Topical formulations comprising:
|
Comparator | Q1: Placebo, no intervention Q2: Oral and injectable formulations of the same intervention Q3: Different concentrations of an intervention (alone or in combination with any other compound) |
Outcomes | Symptoms (e.g., pain reduction) Physical function (e.g., activity limitations and activities of daily living) Treatment response, duration of effect, re-treatment intervals Health-related quality of life Safety-related outcomes (e.g., adverse events, serious adverse events, withdrawal due to adverse events, deaths due to adverse events) |
Study designs | Health technology assessment, systematic reviews, randomized controlled trials |
Articles were excluded if they did not meet the selection criteria outlined in Table 1. SRs in which all relevant studies were captured in other more recent or more comprehensive SRs were excluded. Primary studies retrieved by the search were excluded if they were captured in 1 or more included SRs. Network meta-analyses without comparisons among different formulations (e.g., topical versus oral, or topical versus IV) or among different doses were excluded. Populations with conditions other than osteoarthritis, musculoskeletal (chronic or acute), neuropathy, anal fissures, vulvodynia, pressure ulcers, or cancer-related pain or conditions were excluded. Studies published in a language other than English were also excluded.
The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)16 for SRs, and the revised Cochrane risk-of-bias tool for randomized controlled trials (RoB 2)17. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
A total of 1,072 citations were identified in the literature search. Following screening of titles and abstracts, 941 citations were excluded and 131 potentially relevant reports from the electronic search were retrieved for full-text review. Of these potentially relevant articles, 95 publications were excluded for various reasons, and 36 publications met the inclusion criteria and were included in this report. These comprised 7 SRs and 29 RCTs. Figure 1 of Appendix 1 in the Supplemental Material document presents the PRISMA18 flow chart of the study selection. No potentially relevant publications were retrieved from the grey literature search.
The lists of included and excluded studies with primary reasons for exclusion are presented in Supplemental Material, Appendix 2.
Table 1 to Table 10 of Appendix 3 in the Supplemental Material document provide details regarding the characteristics of the included SRs and primary studies by drug type. For the pain-related conditions of interest (i.e., osteoarthritis, musculoskeletal [chronic or acute], neuropathy, anal fissures, vulvodynia, pressure ulcers, and cancer-related conditions), evidence was identified for 7 of the 8 drugs of interest (i.e., ketamine, ketoprofen, baclofen, clonidine, nifedipine, gabapentin, and diclofenac). No evidence was found for the use of amitriptyline for pain in the conditions of interest.
One SR19 with meta-analysis for neuropathic pain was identified (Table 1 of Appendix 3 in the Supplemental Material document). The study evaluated the benefits and harms of topical ketamine and other NMDA receptor antagonists compared to placebo, usual care, or other medications for adults with chronic pain, particularly neuropathic pain. The SR19 included a total of 67 RCTs, of which 39 RCTs examined the use of ketamine of various formulations, and only 3 RCTs compared topical ketamine versus placebo. Topical ketamine was in the form of a cream with doses of 0.5% to 5%, applied to the affected areas 3 to 4 times per day. The outcomes included pain intensity, disability, and adverse events (AEs). Treatment duration in the 3 included RCTs varied from 2 days to 1 month. The SR19 was conducted by authors in Australia,19 and it was publicly funded (by the UK National Institute for Health and Care Research).
Two SRs20,21 with meta-analysis for osteoarthritis (Table 2 of Appendix 3 in the Supplemental Material document) and 3 RCTs22-24 for acute pain (muscle soreness or ankle sprain) (Table 3 of Appendix 3 in the Supplemental Material document) were identified.
The 2 SRs20,21 compared the efficacy and safety of topical ketoprofen against placebo for improving pain and physical function in adults with knee or hand osteoarthritis. The SR by Wolff et al.20 included 2 RCTs, whereas the SR by Honvo et al.21 included 4 RCTs of topical ketoprofen versus placebo. The SR by Honvo et al.21 only examined the safety of topical ketoprofen. The overlap in relevant primary studies between included SRs20,21 is presented in Table 56 of Appendix 6 in the Supplemental Material document. Ketoprofen was in the form of transferosome gel, with doses of 25 mg, 50 mg, or 100 mg given 2 times per day. The outcomes included pain intensity, physical function, and AEs. Treatment duration varied from 6 weeks to 12 weeks. The 2 SRs were conducted by authors in the US,20 and in Belgium, France, and the UK.21 One SR20 did not report the source of funding, whereas the work of the other20 was publicly funded by the National Research Council of the UK.
Three double-blind, parallel RCTs22-24 compared the efficacy and safety of topical ketoprofen against placebo or oral ketoprofen capsules in adults or children and adolescents with muscle soreness or ankle sprain following exercise or sport activities. Topical ketoprofen was in the form of transferosome gel (100 mg, 200 mg), gel (2.5%, 2 g), or oral capsule (100 mg) given 2 times per day. Treatment duration was 7 days after exercise,22 or 1 time in the emergency department with follow-up of up to 30 minutes.23,24 Pain intensity was assessed using a 10-point Likert scale22 or a 100 mm visual analogue scale (VAS).23,24 Other outcomes included AEs and the need for rescue drugs. The RCTs were conducted by authors in Germany22 and Turkey.23,24 One study22 was funded by a biopharmaceutical company (IDEA AG, Germany), 1 study23 declared that no funding was received, and 1 study24 did not report the source of funding.
Descriptions of the outcomes:
The Likert scale (often called the numerical rating scale [NRS]) is a 10-point pain scale (0 = none to 9 = extremely intense). The minimal important difference (MID) is generally accepted to be 1 to 2 points (or an approximate 30% reduction).25,26
The 100 mm (or 10 cm) VAS is a scale with 0 indicating no pain at the left end and 100 (or 10) indicating maximum imaginable pain at the right end. The MID of VAS for pain is widely recognized as a change of 10 mm to 20 mm (or 1.0 cm to 2.0 cm) on a standard 100 mm (10 cm) scale.27
One double-blind, parallel RCT28 for neuropathic pain was identified (Table 4 of Appendix 3 in the Supplemental Material document).
The RCT28 compared the efficacy and safety of topical baclofen against placebo in adults with type 1 or 2 diabetes mellitus with concomitant diagnosis of peripheral neuropathy based on a neuropathic pain diagnostic questionnaire (Douleur Neuropathique en 4 Questions [DN4] score ≥ 4). Topical baclofen was formulated as a 5% cream, applied 2 times per day. Treatment duration was 3 weeks. The outcomes were neuropathic pain evaluated based on the DN4 10-item questionnaire and possible AEs. The RCT28 was conducted by authors in Iran. The study28 received a grant from a university in Iran.
Description of the outcome:
The DN4 is a 10-item questionnaire divided into 4 groups consisting of 7 questions. This questionnaire includes the pain description (irritation feeling, pain with cold, electric shock feeling), pain-associated sensation (tingling sensation, numbness, itching), and brief examination of the painful areas when touching and scratching the painful area.29 A score of 4 or more is typically used as the cut-off to suggest the presence of neuropathic pain. Because DN4 is used to identify the presence or absence of neuropathic pain rather than to grade its intensity, the concept of a MID does not apply to it.29
One SR30 with meta-analysis for neuropathic pain (Table 5 of Appendix 3 in the Supplemental Material document) and 1 RCT31 for cancer-related oral mucositis (Table 6 of Appendix 3 in the Supplemental Material document) were identified.
The SR30 assessed the analgesic efficacy and safety of topical clonidine compared to placebo in adults with neuropathic pain caused by diabetes. The SR30 included a total of 4 RCTs, of which 3 studies compared topical clonidine 0.1% gel with placebo. The drug was applied 2 to 3 times per day for 8 weeks or 12 weeks. The outcomes were patient-reported pain relief of 50% or greater, patient-reported pain relief of 30% or greater, ratings of “much improved” or “very much improved” on the Patient Global Impression of Change scale (PGIC), and AEs. The SR30 was conducted by authors in Poland and was publicly funded by the National Institute for Health and Care Research in the UK.
The RCT31 evaluated the efficacy and safety of topical clonidine in mitigating chemoradiation-induced oral mucositis in adult patients with head and neck cancer. Topical clonidine was designed as mucoadhesive buccal tablets that locally adhered to the oral mucosa and provided a depot of slow release of the active compound. Patients received a daily local clonidine tablet at 50 mcg, 100 mcg, or placebo starting 1 to 3 days before and continuing during chemoradiation treatment. The outcomes included incidence of severe oral mucositis (grade 3 or 4), duration and time to onset of severe oral mucositis, mouth and throat soreness assessed using the Oral Mucositis Daily Questionnaire (OMDQ), cumulative demand for opioid analgesics, weight loss, AEs, and tolerability. Patient follow-up occurred every 6 months for 2 years. The RCT31 was conducted by authors in France, Germany, Hungary, Spain, Switzerland, and the US. The study was funded by a biopharmaceutical company (BioAlliance Pharma).
Descriptions of the outcomes:
PGIC is a 7-point self-report scale used in clinical trials and practice to measure a patient’s subjective improvement or decline after treatment. It assesses overall changes in activity, symptoms, emotions, and quality of life (QoL), typically ranging from “very much improved” to “very much worse.” Usually, the scale is based on a score of 1 to 7: 1) very much improved, 2) much improved, 3) minimally improved, 4) no change, 5) minimally worse, 6) much worse, and 7) very much worse.32 The MID for PGIC is defined as a score of 5 (“minimally worse”) or lower.33
The OMDQ is a tool used to monitor oral health, often designed for individuals, caregivers, or cancer patients managing side effects like oral mucositis.34 There are 6 questions, each answered on a scale from 1 to 10. For most questions, a higher score indicates a worsening in symptom severity or more interference with functional activity. For the question pertaining to overall health, a higher score indicates better overall health status. The MID for OMDQ is generally recognized as a 10 mm shift on a 0 mm to 100 mm VAS or an equivalent 1-point change on the 0-to-4 or 0-to-10 Likert scales used in OMDQ items.34
Of the 7 identified RCTs that investigated topical nifedipine, 5 RCTs35-39 involved chronic anal fissures, 1 RCT40 involved vulvodynia, and 1 RCT41 involved pressure ulcers (Table 7 of Appendix 3 in the Supplemental Material document). Four of 7 RCTs were open-label,35,36,38,39 1 was single-blind,37 and 2 were double-blind.40,41
For chronic anal fissures, the RCTs35-39 compared the efficacy and safety of topical nifedipine against oral nifedipine or conservative treatment in adult patients. Topical nifedipine was formulated as an ointment or cream at a dose of 0.2% to 2%, applied 2 or 3 times per day. Oral nifedipine was as 10 mg or 20 mg controlled-release tablets, administered 2 or 3 times per day for 4 to 8 weeks. The outcomes included pain intensity assessed using a 10 cm VAS, healing (as evident by complete epithelialization of fissure-bearing area on clinical examination), and AEs. The RCTs were conducted by authors in India35,36,39 and in Iran.37,38 None of the studies reported the source of funding.
One double-blind, parallel RCT40 investigated the efficacy and safety of 2 concentrations of topical nifedipine cream (0.2% and 0.4%) against placebo in adult women with vulvodynia. All patients were administered the cream to the vestibule 4 times per day for 6 weeks. The outcomes were pain intensity assessed using a 100 mm VAS and AEs. The RCT40 was conducted by authors in Israel. The study received funding from a hospital in Israel.
One double-blind, parallel RCT41 evaluated the effect of topical nifedipine 3% ointment against placebo on pressure ulcer healing in critically ill adult patients with stage 1 or 2 pressure ulcers. Approximately 0.5 g of the ointment was administered into and around the edge of the ulcers 2 times per day for 2 weeks. The outcome was ulcer severity (or stage of the ulcers) that was determined by using the 2-digit Stirling Pressure Ulcer Severity Scale. The RCT41 was conducted by authors in Iran. The study41 did not report the source of funding.
Description of the outcome:
The 2-digit Stirling Pressure Ulcer Severity Scale is an observational scale that has 5 stages as follows: 0 = no clinical evidence of a sore; 1 = discoloration of the intact skin; 2 = partial-thickness skin loss; 3 = full-thickness skin loss; and 4 = full-thickness skin loss extending to underlying bone, tendon, or joint capsule.42 There is no established MID for this scale.
One SR43 was identified that narratively synthesized the effectiveness of topical gabapentin in the treatment of vulvodynia from 4 retrospective before-and-after studies (Table 8 of Appendix 3 in the Supplemental Material document). Patients were adult women with chronic vulvar pain. Gabapentin gel was formulated at various concentrations (2%, 4%, 6%). The outcomes were pain intensity assessed using the NRS and AEs. Treatment duration varied from 4 weeks to 24 weeks. The SR43 was conducted by authors in the UK. The SR43 was publicly funded by the Imperial Open Access Fund, Imperial College London.
A total of 4 SRs20,21,44,45 and 17 RCTs46-62 were identified investigating the efficacy and safety of topical diclofenac for various treatment conditions, including osteoarthritis, chronic musculoskeletal pain, acute musculoskeletal pain, and cancer-related pain or conditions.
For osteoarthritis, 4 SRs20,21,44,45 with meta-analysis (Table 9 of Appendix 3 in the Supplemental Material document) and 6 RCTs46-51 (Table 10 of Appendix 3 in the Supplemental Material document; Chronic pain — Osteoarthritis) were identified.
Three SRs20,44,45 compared the efficacy and safety of topical diclofenac against placebo or oral diclofenac tablet for improving pain and physical function in adults with knee or hand osteoarthritis. One SR21 only assessed the safety of topical diclofenac in the management of osteoarthritis. The SRs by Chen et al.44 and by Wolff et al.20 included 12 RCTs, whereas the SR by Honvo et al.21 and by Wiffen and Xia45 included 13 RCTs and 21 RCTs, respectively. The overlap in relevant primary studies between included SRs is presented in Table 56 of Appendix 6 in the Supplemental Material document. Diclofenac was in the form of gel, ointment, patch or plaster, or solution. The concentrations varied among formulations: gel (1% to 3%), solution (1.5%), and patch or plaster (180 mg). Topical diclofenac was applied to the affected areas 2 to 4 times per day. The outcomes included pain intensity, physical function, patient global assessment (PGA), and AEs. The treatment durations varied from 2 weeks to 12 weeks. The SRs were conducted by authors in Belgium, France, and the UK;21 China;44 China and the UK;45 and the US.20 One SR20 did not report the source of funding, 1 SR45 was funded by a biopharmaceutical company (GlaxoSmithKline), and 2 SRs21,44 were publicly funded by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases in Belgium and the Natural Science Foundation of Ningxia Hui Autonomous Region in China, respectively.
Six double-blind or triple-blind parallel RCTs46-51 compared the efficacy and safety of topical diclofenac against placebo in adults with knee osteoarthritis. Topical diclofenac was in the form of a gel (1%) or nano flexible liposomes (0.5 g to 1 g) given 2 to 3 times per day. One RCT51 used diclofenac sodium gel (1.16% and 2.32%) with phonophoresis, applied in 5 sessions per week. Treatment duration varied from 2 weeks to 8 weeks. The outcomes included pain intensity assessed by VAS or Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), stiffness by WOMAC, physical function by WOMAC, and AEs. The RCTs were conducted by authors in China,48 India,47 Iran,46,49,50 and Turkey.51 One study46 declared that no funding was received, 1 study47 received funding from a pharmaceutical company (M/s Life Care Innovations Ltd.), 2 studies48,51 did not report the source of funding, and 2 studies49,50 received funding from a university in Iran.
Descriptions of the outcomes:
PGA is a subjective, patient-reported outcome measure used to evaluate overall disease activity, well-being, or severity of a chronic illness. It is measured using a VAS or an NRS from 0 to 10 (or 0 to 100).63 Lower scores (e.g., ≤ 2.0 on a 0 to 10 scale) generally indicate lower disease activity or better health, while higher scores indicate worse disease severity.
WOMAC is a 24-item, self-administered questionnaire designed to evaluate pain, stiffness, and physical function in patients with hip or knee osteoarthritis, covering 5 pain items, 2 stiffness items, and 17 functional limitation items. Each question is scored 0 to 4 (0 = none, 1 = slight, 2 = moderate, 3 = severe, 4 = extreme), with higher total scores indicating worse pain, stiffness, and functional limitations.64 The MID for total WOMAC ranges from 10 to 12 points on a 0- to 100-point scale.65,66 The MID for the WOMAC pain subscale ranges from 3 to 4 points on a 0- to 20-point scale, or 11 to 21 points when normalized to a 0- to 100-point scale. The MID for the WOMAC stiffness subscale ranges from 1.9 to 2.6 points on a 0- to 8-point scale, or 8 to 13 points when normalized to a 0- to 100-point scale. The MID for the WOMAC physical function subscale ranges from 9 to 12 points on a 0- to 68-point scale, or 13 to 18 points when normalized to a 0- to 100-point scale.
For chronic musculoskeletal pain, 3 parallel RCTs52-54 were identified (Table 10 of Appendix 3 in the Supplemental Material document; Chronic pain — Musculoskeletal).
One RCT52 compared the effect of diclofenac patches (150 mg/day) on the incidence of gastroduodenal ulcers and/or erosions with that of orally administered diclofenac tablets (75 mg/day) in adults with low back pain for 2 weeks. One RCT53 evaluated the efficacy and safety of 75 mg or 150 mg diclofenac patches once daily for 2 weeks in adults with low back pain. The outcomes included pain assessed using VAS, disability assessed using the Roland-Morris Disability Questionnaire, patient satisfaction, global improvement, and AEs. One RCT54 compared the efficacy and safety of diclofenac patches (100 mg/day) with oral diclofenac sustained-release tablets (100 mg/day) in adult patients with chronic musculoskeletal pain conditions for 4 weeks. The outcomes included pain assessed using the NRS, PGIC, and AEs. The RCTs were conducted by authors in India54 and Japan.52,53 One study54 declared that no funding was received, whereas 2 studies52,53 were funded by a pharmaceutical company (Hisamitsu Pharmaceutical Co., Inc., Japan)
Descriptions of the outcomes:
The Roland-Morris Disability Questionnaire (RMDQ) is a 24-item patient-reported outcome measure that inquires about pain-related disability resulting from low back pain. Items are scored 0 if left blank or 1 if endorsed, for a total RMDQ score ranging from 0 to 24; higher scores represent higher levels of pain-related disability.67 The MID for the RMDQ is accepted as an improvement of 3 to 5 points, or a 30% reduction from the patient's baseline score.
Patient satisfaction is rated by how satisfied patients are with the analgesic treatment for their low back pain in the past week by using 5 categories: “very satisfied,” “satisfied,” “neither satisfied nor unsatisfied,” “unsatisfied,” and “very unsatisfied.” The minimum important change is generally defined as an improvement of at least 1 full category.68
Global improvement is rated by the investigator using 5 categories: “much improved,” “improved,” “unchanged,” “aggravated,” and “very aggravated”; the rating is based on a combined assessment of changes from baseline in pain VAS score and RMDQ score, the degree of patient satisfaction, and physical findings. There is no single established MID.
PGIC is a 7-point self-report scale used in clinical trials and practice to measure a patient’s subjective improvement or decline after treatment. It assesses overall changes in activity, symptoms, emotions, and QoL, typically ranging from “very much improved” to “very much worse.” Usually, the scale is based on a score of 1 to 7: 1) very much improved, 2) much improved, 3) minimally improved, 4) no change, 5) minimally worse, 6) much worse, and 7) very much worse.32 The MID for PGIC is defined as a score of 5 (“minimally worse”) or lower.33
For acute musculoskeletal pain, 1 SR45 (Table 9 of Appendix 3 in the Supplemental Material document) and 6 parallel RCTs55-60 (Table 10 of Appendix 3; Acute pain — Musculoskeletal in the Supplemental Material document) were identified.
The SR45 included 23 RCTs that evaluated the efficacy and safety of topical diclofenac compared with placebo in adolescents and adults (mean age: 16 to 63 years) with acute musculoskeletal pain of at least moderate intensity resulting mainly from strains, sprains, and contusions, usually as a result of sport injuries. Topical diclofenac was in the form of a gel (1% to 3%) or patch or plaster (180 mg) applied 2 to 4 times per day. Treatment duration varies from 5 days to 3 weeks, with 1 to 2 weeks in most studies. The outcomes were clinical success (defined as at least a 50% reduction in pain intensity) and AEs. The SR45 was conducted by authors in China and the UK. The SR45 was funded by a biopharmaceutical company (GlaxoSmithKline).
The 6 RCTs55-60 assessed the efficacy and safety of topical diclofenac of various formulations compared with placebo or different doses in adolescents or adults with acute pain of the limbs (strains, sprains, and contusions) or with acute back and neck pain, usually from sport injuries. Topical diclofenac was in different forms, including gel (1.16% to 6%) and patch or plaster (140 mg) of different compounds such as diclofenac sodium, diclofenac potassium, or diclofenac diethylamine. The drug was applied 1 to 4 times per day for a treatment period of 5 days to 4 weeks. The outcomes included pain intensity (assessed by VAS, NRS, or WOMAC), stiffness and physical function (assessed by WOMAC), response (defined as at least 50% decrease in VAS), Clinical Global Impressions–Improvement (CGI-I), ankle tenderness, joint function, swelling, patient-reported pain intensity, and pain relief, global assessment of the response to treatment, overall efficacy, and AEs. The RCTs were conducted by authors in China;57 France and Germany;58 Germany;59,60 Germany, Hungary, and Italy;55 and Saudi Arabia.56 One study56 was publicly funded by a university in Saudi Arabia, while 5 studies55,57-60 received funding from biopharmaceutical companies (Fidia Farmaceutici S.p.A., GlaxoSmithKline, Boehringer Ingelheim Pharma GmbH & Co.)
Descriptions of the outcomes:
CGI-I is a 7-point scale that is summarized in 3 categories: improvement (including very much improved, much improved, minimally improved), no change and worsening (minimally worse, much worse, very much worse). The MID for CGI-I is anchored at a score of 3 (“minimally improved”).69
Ankle tenderness is measured using a pressure pain metre (algometer) that is applied in an area of 1 cm2 at the centre of the injured area; the patient indicates with a verbal cue when the onset of pain occurred.70
Ankle function is measured using the Karlsson Ankle Function Score (often referred to as the Karlsson-Peterson scale), a 90‑point, 8-item questionnaire used to assess ankle function, focusing on pain, stability, and activities of daily living. A higher score indicates better ankle function, with 90 points representing no impairment. The MID for the Karlsson Ankle Function Score is approximately 10 points.71
Ankle swelling is measured using the figure-of-eight technique by measuring circumference with a tape measure.72
Patient-reported pain intensity and pain relief: Patients completed a pain diary, which included pain intensity measured on a 4‑point scale (0 = no pain to 3 = severe pain) and spontaneous pain relief assessed on a 5-point scale (0 = no relief to 4 = complete relief). The MID is any improvement of at least 1 point category.73
Global assessment of the response to treatment is assessed using a 5-point scale: 0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent. The MID is 1 point.
Overall efficacy is assessed using a 5-point scale: 1 = none, 2 = poor, 3 = fair, 4 = good, and 5 = excellent. The MID is 1 point.
For cancer-related pain or conditions, 2 double-blind parallel RCTs61,62 were identified (Table 10 of Appendix 3 in the Supplemental Material document; Acute pain — Cancer-related pain or conditions).
One RCT61 assessed the efficacy and safety of topical diclofenac in the prevention of capecitabine-induced hand-foot syndrome (HFS) compared with placebo. HFS is a dose-limiting side effect of capecitabine, an oral chemotherapy medication, and is characterized by redness, swelling, and pain on the palms of the hands and soles of the feet. Patients were adults with breast or gastrointestinal (GI) cancer who planned to receive capecitabine-based treatment. Topical diclofenac was in the form of a 1% gel, with approximately 1 g applied to each hand or foot 2 times per day for 12 weeks or until development of HFS. The outcomes included incidence of grade 2 or 3 HFS, development of grade 1 to 3 HFS, HFS-related dose changes of capecitabine, time to the development of HFS, adherence to topical application, HFS-related QoL, and AEs. The RCT61 was conducted by authors in India. The study61 was funded by a pharmaceutical company (Alkem Laboratories Limited).
One RCT62 evaluated the efficacy and safety of diclofenac patches compared to placebo for the treatment of cancer pain. Patients were adults with an established diagnosis of cancer of the lung, pancreas, stomach, breast, prostate, colon, esophagus, or other sites. The study consisted of a 2-week to 4-week open-label dose-titration phase and a 4-week double-blind phase. During the dose-titration phase, the dose was started at 150 mg/day (2 × 75 mg patches a day) and could then be increased up to 225 mg (3 × 75 mg patches a day) if necessary to achieve an analgesic effect. During the double-blind phase, patients received either diclofenac sodium patches at the same dose as at the end of the dose-titration phase or placebo for 4 weeks. The outcomes included the time to insufficient analgesic response during the double-blind phase, quality of sleep, patient satisfaction, pain relief, pain intensity, and AEs. The RCT62 was conducted by authors in Japan. The study62 was funded by a pharmaceutical company (Hisamitsu Pharmaceutical Co., Inc.).
Description of the outcomes:
HFS (or palmar-plantar erythrodysesthesia) is graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. Grade 1 (mild): minimal skin changes, or redness or swelling; no pain; no interference with daily activities. Grade 2 (moderate): noticeable peeling, blisters, bleeding, or thickening (hyperkeratosis); mild-to-moderate pain; and pain limiting instrumental activities of daily living (such as shopping, preparing meals, or cleaning). Grade 3 (severe): severe changes including heavy peeling, severe blistering, bleeding, or fissuring; severe pain; pain that prevents or limits basic activities of daily living (such as bathing, dressing, or basic self-care). Grade 4 (very severe): ulceration, extensive blistering, and severe cracking; and inability to perform basic tasks or walk.74
HFS-related QoL is assessed using the HFS14 questionnaire, a validated, 14-item specific questionnaire that measures impairment across 3 primary domains: hand disability, feet disability, and social impact. Each item is scored on a 3-point Likert scale ranging from 0 to 2, or sometimes 0 to 6 depending on the exact adjustment scale. The raw score is adjusted to a scale of 0 to 100. A score closer to 0 indicates no QoL impairment, whereas a score closer to 100 reflects the highest level of impairment.75
Insufficient analgesic response was defined as more than 15 mm worsening on the VAS score at the time when patients asked to withdraw from the study — if the reason for their request was insufficient analgesic response — compared with the mean VAS score on the 3 days before transition to the double-blind phase.
Physicians rated the quality of sleep as “very good sleep,” “good sleep,” “poor sleep,” or “very poor sleep” at the baseline examination, the final assessment during the dose-titration phase, and the final assessment during the double-blind phase.
Physicians rated patient satisfaction in the past week as “very satisfied,” “satisfied,” “neither satisfied nor dissatisfied,” “dissatisfied,” and “very dissatisfied” at the final assessment of the dose-titration phase and the double-blind phase.
Physicians asked patients to compare their pain relief with baseline by using the 6 categories “complete relief,” “strong relief,” “moderate relief,” “slight relief,” “no relief,” and “worsening.”
Patients were asked to rate their pain intensity at the assessment site on each visit day from the baseline examination to the final assessment during the double-blind phase by using the 4 categories “none,” “mild,” “moderate,” and “severe.”
Table 11 of Appendix 4 in the Supplemental Material document presents the detailed descriptions of the strengths and limitations of the SRs19-21,44,45 assessed using AMSTAR 2.16 Briefly, 3 SRs19,21,44 were robust in methodology that fulfilled most of the items in AMSTAR 2, whereas 2 SRs20,45 had various limitations, including risk of bias in reporting, study selection, study extraction, analysis, and interpretation of the results. We summarized the risk of bias of the primary studies assessed by the authors of each SR and presented it alongside the summary of findings.
We used RoB 217 to assess the risk of bias for each of the included RCTs (Table 12 to Table 41 of Appendix 4 in the Supplemental Material document). We summarized the risk of bias of each included RCT and presented it alongside the summary of findings.
Table 42 to Table 55 of Appendix 5 in the Supplemental Material document present the main study findings. The findings are presented by disease conditions and divided into 2 main categories: chronic pain and acute pain. Chronic pain is defined as pain that persists or recurs for longer than 3 months. Pain associated with osteoarthritis, chronic musculoskeletal disorders, neuropathy, anal fissures, vulvodynia, and pressure ulcers is classified as chronic pain. Pain associated with acute musculoskeletal injuries and cancer-related pain or conditions is classified as acute pain.
Four SRs20,21,44,45 and 6 RCTs46-51 examining 2 drugs (i.e., ketoprofen and diclofenac) provided evidence on the treatment of osteoarthritis in adults, mainly of the knee. The risk of bias of the included studies is presented first, followed by a description of the summary of findings.
Table 2 in this report presents the results of quality and bias assessment of the studies included in the SRs20,21,44,45 for osteoarthritis. The assessments were conducted by the authors of the SRs.20,21,44,45
The SR by Wolff et al.20 included 18 RCTs, of which 3 RCTs were for topical ketoprofen and 12 RCTs were for topical diclofenac. The authors of the SR20 used the Jadad score to assess the quality of the RCTs. Overall, most RCTs (83%) had a maximum score of 5, 2 RCTs (11%) had a score of 4 (blinding and randomization procedures not reported), and 1 RCT (3.8%) had a score of 2 (lack of blinding procedures).
The SR by Honvo et al.21 included 4 RCTs for ketoprofen and 11 RCTs for diclofenac. The authors of the SR21 used the original Cochrane Collaboration risk-of-bias tool (RoB 1) to assess the quality of the RCTs.
For ketoprofen, all included RCTs had a high risk of bias in selective reporting (reporting bias), but they had a low risk of bias in incomplete outcome data (attrition bias). Most RCTs (75%) had unclear risk of bias in the blinding of the assessor (detection bias) and in allocation concealment (selection bias).
For diclofenac, most studies (55% to 91%) had a low risk of bias in randomization and allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of assessor (detection bias), and incomplete outcome data (attrition bias). Nearly half of the RCTs (45%) had a high risk of bias in selective reporting (reporting bias).
The SR by Chen et al.44 included 12 RCTs for diclofenac. The authors of the SR44 used RoB 2 to assess the quality of the RCTs. Most RCTs (75%) demonstrated a low risk of bias for any RoB 2 items, and all studies (100%) showed a low risk of bias for selective reporting.
The SR by Wiffen and Xia45 included 21 RCTs for diclofenac. The authors of the SR45 used RoB 1 to assess the quality of the RCTs. All RCTs were randomized and double-blind. The main limitations were the study duration and study sample size. Nearly half of the RCTs (48%) had a high risk of bias in study duration, and 19% of the RCTs had a high risk of bias in study sample size. Treatments for chronic conditions generally need to be proven effective over longer periods of time. By the authors’ definitions, studies were assessed to be at a low risk of bias if they were conducted for 6 weeks or more, and studies were assessed to be at a high risk of bias if they were conducted for 4 weeks or less. For sample size bias, small studies tend to overestimate the treatment effects. As such, the authors of the SR45 determined that studies with at least 200 participants per treatment arm were assessed to be at a low risk of bias, and studies were assessed to be at a high risk of bias if they had fewer than 50 participants per treatment arm.
Table 3 in this report presents the summary results of the risk-of-bias assessment of the included primary studies46-51 for diclofenac. We used RoB 2 to assess the risk of bias of the RCTs. Five46,47,49-51 of 6 RCTs were double-blind, and 1 RCT48 did not report the blinding status. All studies (100%) had a low risk of bias for missing outcome data and for selection of reported results. Most studies (83%) had a low RoB in measurement of outcome. Overall, 1 RCT (17%) had a high risk of bias, 1 RCT (17%) raised some concerns (unclear risk of bias), and 4 RCTs (66%) had a low risk of bias.
Ketoprofen: The SR by Wolff et al.20 included 2 RCTs, and the SR by Honvo et al.21 included 4 RCTs for topical ketoprofen that provided data for meta-analysis. The RCTs assessed the efficacy and safety of topical ketoprofen for the treatment of knee osteoarthritis in adults. The main study characteristics and key findings are summarized in Table 4 in this report. Table 42 in Appendix 5 of the Supplemental Material document presents more details of the findings.
Key findings in the SR by Wolff et al.:20
For pain relief, topical ketoprofen (transferosome gel) exhibited a small effect size, meaning that it may result in little to no difference in improving pain compared to placebo.
Topical ketoprofen may result in a moderate effect size for improvement of physical function compared to placebo.
AEs of topical ketoprofen were mostly associated with skin and soft tissue disorders. There were little to no differences between topical ketoprofen and placebo with respect to GI disorders or cardiovascular disorders.
Key findings in the SR by Honvo et al.:21
Overall, there were little to no differences in the rate of total AEs between topical ketoprofen (transferosome gel) and placebo.
There was a tendency for more withdrawals due to AEs observed in the topical ketoprofen group compared to the placebo group.
Topical ketoprofen may result in a lower incidence of nervous system disorders (e.g., headache) compared to placebo.
There were little to no differences between groups in terms of cardiovascular disorders, musculoskeletal and connective tissue disorders, serious AEs, or severe AEs.
Diclofenac: The SRs by Wolff et al.,20 Honvo et al.,21 Chen et al.,44 and Wiffen and Xia45 included 9 RCTs, 8 RCTs, 12 RCTs, and 18 RCTs, respectively, for the comparison of clinical efficacy and safety between topical diclofenac and placebo. The main study characteristics and key findings are summarized in Table 4 in this report. Table 43 in Appendix 5 of the Supplemental Material document presents more details of the findings.
Key findings in the SR by Wolff et al.:20
For pain relief, topical diclofenac (gel, solution, and patch) showed a moderate effect size compared to placebo.
For functional improvement, topical diclofenac also showed a moderate effect size compared to placebo.
Key findings in the SR by Honvo et al.:21
Topical diclofenac (gel, solution, and patch) treatment resulted in an increase in total AEs compared to placebo.
The rate of withdrawal due to AEs was twice as high with topical diclofenac compared to placebo.
The higher rate of total AEs associated with topical diclofenac appeared to be driven by higher rates in skin and subcutaneous disorders compared to placebo.
There were no differences between groups in GI disorders or serious AEs.
Key findings in the SR by Chen et al.:44
Topical diclofenac (gel, solution, and patch) showed improvement in pain compared to placebo in the short term (1 to 2 weeks), medium term (3 to 6 weeks), and long term (8 to 12 weeks).
Topical diclofenac also showed improvement in physical function and stiffness compared to placebo.
Overall disease activity (PGA scores) reported by patients was better with topical diclofenac compared to placebo.
There were no differences in AEs between topical diclofenac and placebo in terms of skin disorders, GI disorders, and withdrawals due to AEs.
Key findings in the SR by Wiffen and Xia:45
Patients in the topical diclofenac (gel, solution, and patch) groups experienced a higher clinical success rate (defined as at least a 50% reduction in pain intensity) compared to control. The number needed to treat (NNT) was 9.5, indicating that for every 10 patients treated with topical diclofenac, 1 will experience a clinical success.
The rate of local AEs, including dry skin, redness, or erythema, and itch or pruritus, was slightly higher in the topical diclofenac groups compared to placebo. The number needed to harm (NNH) was 20, indicating that for every 20 patients who receive topical diclofenac, 1 will experience a local AE that would not occur in the placebo group.
The rate of withdrawal due to AEs was also slightly higher in the topical diclofenac groups compared to placebo. The NNH was 54. So, for every 54 patients who received topical diclofenac, 1 would withdraw from treatment due to AEs that would not occur in the placebo group.
There were no differences between topical diclofenac and placebo in the incidence of systemic AEs (headache, diarrhea, drowsiness, and dyspepsia) or serious AEs.
Six RCTs46-51 that were identified and included in this review provided evidence on the clinical efficacy and safety of topical diclofenac (mostly gel formulations of different doses) for the treatment of knee osteoarthritis from 2 weeks to 8 weeks. Overall, all studies showed that topical diclofenac was effective for pain relief, stiffness, and physical function improvement compared to placebo. The key findings are summarized in Table 4 in this report. Table 44 in Appendix 5 of the Supplemental Material document presents more details of the findings.
Key findings:
Three RCTs by Abbasifard et al.46 Dehghan et al. (2019),49 and Dehghan et al. (2020)50 showed that, after 6 to 8 weeks of treatment, diclofenac gel 1% improved pain, stiffness, and physical function compared to placebo. No serious AEs, treatment-related AEs, or withdrawal due to AEs were observed.
The RCT by Bhatia et al.47 showed that, after 6 weeks of treatment, both topical diclofenac formulations (liposomal gel 20 g or Emulgel 20 g) were effective for knee osteoarthritis. Both types of gel showed marked improvement in pain, stiffness, and physical function compared to placebo. No skin or GI disorders were observed during the study period.
The RCT by Li et al. demonstrated that diclofenac nanoliposome gel reduced pain and swelling of the knee and improved knee joint mobility after 1 week and 2 weeks of treatment. No major skin or GI disorders were recorded during the study period.
The RCT by Tolu et al.51 showed that diclofenac sodium phonophoresis gel of 2 different concentrations (1.16%, 2.32%) improved pain, stiffness, and physical function compared to placebo after 2 weeks of treatment. No treatment-related AEs were observed during the study period.
Diclofenac: The SR by Wiffen and Xia45 included 3 RCTs that contributed to the analysis comparing topical diclofenac (1.16% gel or 1.5% solution) against oral diclofenac slow-release 100 mg tablet for 3 weeks to 12 weeks. The key findings are summarized in Table 4 in this report. Table 43 in Appendix 5 of the Supplemental Material document presents more details of the findings.
Key findings:
The response rates (defined as greater than 50% pain relief) were similar for both treatments.
Local AEs (dry skin, redness or erythema, and itch or pruritus) were more frequent with topical diclofenac than with oral diclofenac. The NNH for local AEs was 4.3, indicating that for every 4 patients using topical diclofenac, 1 will experience a local AE that would not have occurred with oral diclofenac.
Systemic AEs such as GI disorders were more common with oral diclofenac than with topical diclofenac. The NNH for GI was 8, indicating that for every 8 patients who take oral diclofenac, 1 will experience a GI AE that would not have occurred with topical diclofenac.
There was no difference between topical diclofenac and oral diclofenac with respect to withdrawal due to AEs. However, it appeared that the proportion of patients withdrawing from topical diclofenac due to lack of efficacy was higher than the proportion withdrawing from oral diclofenac.
The authors of the SR45 noted that there were too few events of serious AEs to draw any conclusions.
Diclofenac: The RCT by Tolu et al.51 showed that diclofenac sodium phonophoresis 2.32% gel was more effective in reducing pain and improving stiffness and physical function compared to diclofenac sodium phonophoresis 1.16% gel. No treatment-related AEs were observed.
Evidence on topical ketoprofen versus placebo was derived from fewer RCTs compared to topical diclofenac for treatment of osteoarthritis. The studies of topical ketoprofen included in the SRs had a high risk of bias in selective reporting, and the analysis showed that topical ketoprofen resulted in little to no difference compared to the carrier (i.e., transferosome) in reducing pain and improving physical function in adults with knee osteoarthritis. In other words, the carrier transferosome showed noninferior performance to the ketoprofen preparation, given that both were able to reduce pain scores from baseline to the end of treatment in the same manner. This suggests a strong placebo effect of transferosome for the treatment of pain. Future studies should incorporate objective measures such as radiography or the measurement of inflammatory markers to further investigate the effect of topical drugs on disease progression. There was no evidence regarding the comparative efficacy of topical ketoprofen versus oral ketoprofen (Question 2), or the comparative efficacy of different concentrations of topical ketoprofen (Question 3).
For topical diclofenac, ample evidence from a large number of methodologically sound studies demonstrated a moderate effect size for reducing pain and improving physical function in the treatment group compared to placebo. While the included studies demonstrated a low risk of bias, particularly for selective reporting bias, most studies were sponsored by manufacturers, which may have introduced potential bias in the interpretation of the results. As such, the findings that topical diclofenac was effective for pain relief in patients with osteoarthritis compared to placebo should be interpreted with caution. The included studies varied in treatment duration, study sizes, patient characteristics, and evaluation methods, which may contribute to the heterogeneity of the results. All of the 6 included RCTs were small, with study sizes fewer than 50 patients per treatment arm, which tends to overestimate the treatment effects. In terms of safety, in their SR, Honvo et al.21 commented that they were unable to draw a definitive conclusion regarding the AEs of different topical formulations and daily doses, given that these parameters may influence the absorption and safety of topical treatment. In addition, the reporting of AEs was generally poor in most studies, despite the fact that AEs were low in number and mild to moderate in nature. Long-term safety profiles of topical diclofenac may be different from those of short-term use. The longest treatment duration of the studies included in the SRs and in the included RCTs was 12 weeks. Therefore, longer-term safety and tolerability of topical diclofenac need further investigation.
Three RCTs52-54 provided evidence on the clinical efficacy and safety of topical diclofenac for the treatment of chronic musculoskeletal pain. The risk of bias of the included studies is presented first, followed by a description of the summary of findings.
Table 5 in this report presents the summary results of the RoB assessment of the included primary studies.52-54 We used RoB 2 to assess the risk of bias of those RCTs. One RCT52 was assessor-blinded, 153 was double-blind, and 154 was open-label. Overall, 1 RCT53 had a low risk of bias, 1 RCT52 had some concerns (unclear risk of bias), and 1 RCT54 had a high risk of bias.
Table 6 in this report presents the main study characteristics and key findings of the studies evaluating topical diclofenac for chronic musculoskeletal pain. Table 22 in Appendix 5 of the Supplemental Material document presents more details of the findings.
Key findings:
The RCT by Taguchi et al.53 found that both doses of diclofenac sodium patch (75 mg and 150 mg) may result in better pain relief compared to placebo after 2 weeks of treatment. For other outcomes such as response (≥ 50% improvement in pain), disability, patient satisfaction, and global improvement, both doses of diclofenac sodium patch achieved better results than placebo. Most AEs were mild and comparable among groups. No serious AEs were observed.
Key findings:
The RCT by Fukase et al.52 compared the effect of topical diclofenac sodium patch (2 × 75 mg) on the upper GI mucosa with that of oral diclofenac sodium tablet (75 mg) in patients with low back pain. After 2 weeks of treatment, the incidence of GI ulcers and/or erosions was lower in the diclofenac patch group than in the oral diclofenac tablet group. No serious AEs or withdrawals due to AEs were observed.
The RCT by Shinde et al.54 showed that the diclofenac patch (100 mg) and oral diclofenac 100 mg sustained-release tablet had similar efficacy in reducing pain at the end of 4 weeks of treatment in patients with chronic musculoskeletal pain. Both treatments did not differ in terms of global improvement assessed by PGIC. The incidence of total AEs (20% versus 29.2%) and the incidence of epigastric pain or burning sensation in the abdomen (4% versus 8.3%) were numerically lower in the diclofenac patch group than in the oral diclofenac tablet group, although statistical comparisons were not conducted.
The RCT by Taguchi et al.53 found that both doses of diclofenac sodium patch (75 mg and 150 mg) did not differ from each other for all outcomes, such as pain reduction, response, disability, patient satisfaction, global improvement, and total AEs.
The 3 RCTs52-54 that provided evidence on topical diclofenac for chronic musculoskeletal pain had some limitations. First, there was only 1 study53 of topical diclofenac that compared the efficacy and safety of diclofenac patch with placebo for low back pain. The study treatment duration was only 2 weeks, and as such, the efficacy and safety in patients treated on a long-term basis is unclear. Second, there were 2 studies52,54 with small sample sizes that compared the efficacy and/or safety of topical diclofenac against oral diclofenac for low back or other chronic musculoskeletal pain. Studies with small sample sizes may overestimate the treatment effects. In addition, the duration of treatment in those studies was 2 weeks and 4 weeks, which is relatively short for any treatment of chronic musculoskeletal pain. The incidence of AEs and tolerability of both topical diclofenac patch and oral diclofenac tablet may have been higher than expected in the clinical settings. Third, the populations in all 3 included RCTs52-54 consisted largely of patients younger than 65 years and may be biased toward a relatively younger population than the patients who are likely to require treatment for low back pain and other musculoskeletal pain in a clinical setting. Fourth, while no direct evidence of selective reporting bias was identified in 2 RCTs,52,53 the potential bias associated with manufacturer sponsorship requires attention when interpreting the results.
Two SRs (1 examining ketamine,19 1 examining clonidine,30) and 1 RCT28 examining baclofen provided evidence on topical treatment for neuropathic pain. The risk of bias of the included studies is presented first, followed by a description of the summary of findings.
Table 7 in this report presents the results of quality and bias assessment of the studies included in the SRs19,30 for neuropathic pain. The assessments were conducted by the authors of the SRs.19,30
The SR by Ferraro et al.19 included 3 RCTs for ketamine. The authors of the SR19 used RoB 2 to assess the quality of the RCTs. Overall, all 3 RCTs demonstrated a high risk of bias for missing outcome data.
The SR by Serednicki et al.30 included 4 RCTs for clonidine. The authors of the SR30 used the RoB 1 to assess the quality of the RCTs. None of the studies had a low risk of bias in all domains. One study had a high risk of bias for blinding of participants and personnel. Two studies had a high risk of bias for incomplete outcome data. One study had a high risk of bias for selective reporting. Three studies had a high risk of funding bias. All of the included studies were assessed as having some concerns (unclear risk of bias) for allocation concealment, blinding of outcome assessment, and study size. Two studies were assessed as having some concerns (unclear risk of bias) for random sequence generation and blinding of participants and personnel.
Table 8 in this report presents the summary results of the risk-of-bias assessment of the included primary study28 for neuropathic pain. We used RoB 2 to assess the risk of bias of the RCT. Overall, the included RCT28 had a high risk of bias, particularly for missing outcome data.
Table 9 in this report presents the main study characteristics and key findings of the studies evaluating topical interventions (ketamine, baclofen, clonidine) for neuropathic pain. Table 23, Table 24, and Table 25 in Appendix 5 of the Supplemental Material document present more details of the findings.
Ketamine: The SR by Ferraro et al.19 included 3 RCTs evaluating the efficacy and safety of topical ketamine compared to placebo for the treatment of neuropathic pain.
Key findings:
There was no clear evidence of an effect of topical ketamine compared to placebo on the reduction of pain in the immediate term (2 days) or in the short term (4 weeks).
No studies reported data on pain intensity in the medium term or in the long term.
There was no clear evidence that patients receiving topical ketamine were more likely to experience AEs or to withdraw from treatment due to AEs than patients receiving placebo.
No serious AEs were observed.
Baclofen: The RCT by Ala et al.28 evaluated the analgesic effect of topical baclofen 5% cream against placebo in neuropathic pain.
Key findings:
Pain intensity decreased in both groups in any of the follow-up visits compared to baseline.
Topical baclofen appeared to have a better outcome in pain reduction after 3 weeks of treatment compared to placebo.
After adjustment for sex and underlying disease, there were no differences between groups for pain intensity assessed by DN4 scores.
No AEs were observed.
Clonidine: The SR by Serednicki et al.30 included 3 RCTs in the analysis evaluating the efficacy and safety of topical clonidine 0.1% gel compared to placebo for chronic neuropathic pain.
Key findings:
There was no clear evidence of a difference between groups for patient-reported pain relief of 50% or greater during the 12-week treatment period.
Patients treated with topical clonidine were more likely to experience at least a 30% pain reduction compared to those receiving placebo during the 8- to 12-week treatment period.
There was no evidence of a difference between groups for the improvement (“very much,” “much,” or “very much”) on PGIC during the 12-week treatment period.
There was no evidence of a difference between groups for total AEs, withdrawal due to AEs, withdrawal due to lack of efficacy, or serious AEs during the 12-week treatment period.
Evidence on treatment of neuropathic pain with topical ketamine, topical baclofen, and topical clonidine was very limited. The SR by Ferraro et al.19 included only 3 RCTs examining the use of topical ketamine versus placebo. According to the authors of the SR,19 the certainty of evidence on all outcomes assessed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was low and very low due to a limited number of small studies with imprecise estimates.
The study by Ala et al.28 evaluating the efficacy and safety of topical baclofen had a high risk of bias for missing outcome data, given that 18% of patients in the placebo group were lost to follow-up. Patient characteristics with respect to sex and comorbidities were not balanced between groups, which can affect the results due to the difference in pain thresholds.
The SR by Serednicki et al.30 also included only 3 RCTs examining the use of topical clonidine versus placebo. According to the authors of the SR,30 the certainty of the evidence for most outcomes was very low.
Overall, the included RCTs for ketamine, baclofen, and clonidine were not designed to robustly evaluate the long-term efficacy and safety of the drugs for chronic neuropathic pain, because the studies had small patient samples and brief treatment and follow-up periods. Given that the treatment duration of the included RCTs varied from 2 days to 12 weeks, the longer-term effects of the interventions were uncertain. The included RCTs did not provide clear methods for AE assessment and classification. Therefore, the clinical relevance of these studies was limited, and the findings should be considered exploratory.
Five RCTs (4 open-label,35,36,38,39 1 single-blind37) provided evidence on the use of topical nifedipine in the treatment of anal fissures. The risk of bias of the included studies is presented first, followed by a description of the summary of findings.
Table 10 in this report presents the summary results of the risk of bias assessment of the included primary studies35-39 for anal fissure-related pain. We used RoB 2 to assess the risk of bias of the RCTs. Overall, all of the included RCTs35-39 had a high risk of bias, mainly for the measurement of the outcome (detection bias). Because most studies were open-label, the person assessing or measuring the outcome was aware of the participant's treatment or exposure status, which can lead to over- or underestimating the results. Two studies37,38 demonstrated a high risk of bias for missing outcome data (attrition bias).
Table 11 in this report presents the main study characteristics and key findings of the studies evaluating topical nifedipine for chronic anal fissures. Table 26 in Appendix 5 of the Supplemental Material document presents more details of the findings.
The RCT by Agrawal et al.35 compared the effect of the addition of topical nifedipine 0.2% ointment to conservative measures (fibre, stool softener, lignocaine) to conservative treatment alone for 8 weeks for the treatment of anal fissures.
Key findings:
The addition of topical nifedipine 0.2% ointment to the conservative treatment may result in better pain relief and patients may achieve a higher rate of ulcer (fissure) healing compared to conservative treatment alone. The results were reported graphically.
There was no evidence of a difference between groups in the incidence of total AEs or headaches.
The RCT by Golfam (2010)37 compared the efficacy and safety of topical nifedipine against conservative treatment (stool softeners and lidocaine 2% cream) for 4 weeks.
Key findings:
Topical nifedipine 0.5% cream may result in a higher rate of pain relief and complete ulcer healing compared to conservative treatment.
There was no evidence of a difference between groups for anal fissure recurrence rate within the first 2 months of follow-up.
Topical nifedipine was associated with mild headaches in 4 patients (6.7%).
The RCT by Bhatia36 compared the effect of topical nifedipine 2% cream versus oral nifedipine tablets (10 mg) for 4 weeks.
Key findings:
Topical nifedipine 2% cream may result in a higher rate of pain relief and ulcer healing compared to oral nifedipine tablets. However, there is no evidence of a difference between groups for overall effectiveness (pain relief and healing).
AEs were not reported in the study.
The RCT by Sinha and Kumar39 compared the effect of topical nifedipine 0.2% ointment versus oral nifedipine tablets (10 mg) for 8 weeks.
Key findings:
There was no evidence of a difference between topical nifedipine ointment and oral nifedipine tablets for pain relief or ulcer healing.
AEs were not reported in the study.
The RCT by Agrawal et al.35 compared the efficacy and safety of topical nifedipine 0.2% ointment with oral nifedipine tablets (20 mg) in combination with conservative treatment, for 8 weeks.
Key findings:
There was no evidence of a difference between topical nifedipine ointment and oral nifedipine tablets for pain relief or ulcer healing.
There was no evidence of a difference between topical nifedipine ointment and oral nifedipine tablets for any AEs or headaches.
The RCT by Golfam et al. (2014)38 compared the effect of topical nifedipine 0.5% cream versus oral nifedipine tablets (10 mg) for 4 weeks.
Key findings:
There was no evidence of a difference between topical nifedipine cream and oral nifedipine tablets for pain relief.
Nifedipine cream may result in a higher rate of ulcer healing compared to oral nifedipine tablets.
There was no evidence of a difference between groups for recurrence rates of anal fissures after 6 months of follow-up.
Headache and flushing were more frequent with oral nifedipine.
Evidence on the treatment of anal fissures using topical nifedipine was derived from 5 RCTs of low methodological quality, all of which demonstrated a high risk of bias, particularly for the measurement of outcomes. None of the studies reported the source of funding. As such, it was unclear if there was any interpretation bias associated with the manufacturer’s sponsor. Study sizes were small (30 to 62 patients per arm). Small studies have been shown to overestimate treatment effects, probably due to methodological weaknesses.
One SR43 and 1 RCT40 provided evidence on topical interventions (gabapentin, nifedipine) in the treatment of chronic vulvodynia. The risk of bias of the included studies is presented first, followed by a description of the summary of findings.
Table 12 in this report presents the results of quality and bias assessment of the studies included in the SR43 for vulvodynia. The assessments were conducted by the authors of the SR.43
The SR by Ergisi et al.43 included 4 retrospective before-after studies without control arms. Using the National Heart, Lung, and Blood Institute tool, the quality was rated poor in 2 studies and fair in the other 2 studies.
Table 13 in this report presents the summary results of the risk-of-bias assessment of the included primary study40 for vulvodynia. We used RoB 2 to assess the risk of bias of the RCT40 and, overall, it had some concerns (unclear risk of bias) regarding the selection of reported results.
Table 14 in this report presents the key findings of the studies evaluating topical gabapentin and topical nifedipine for chronic vulvodynia. Table 27 and Table 28 in Appendix 5 of the Supplemental Material document present more details of the findings.
In the SR by Ergisi et al.,43 all included before-after studies reported improvement in pain measures after treatment with topical gabapentin. However, the authors of the SR43 noted that conclusions could not be made due to methodological heterogeneity and inherent limitations.
The RCT by Bornstein et al.40 investigated the efficacy and safety of 2 concentrations (0.2% and 0.4%) of topical nifedipine cream versus placebo for treatment of vulvodynia for 6 weeks.
Key findings:
There was no evidence of a difference in pain relief in all 3 groups after 6 weeks of treatment, or after 12 weeks of follow-up.
Mild irritation was felt by some of the participants in both nifedipine groups, but not in the placebo group. The irritation ceased with continued use of the ointment.
The RCT by Bornstein et al.,40 did not provide any evidence of a difference in pain relief between the 2 concentrations of topical nifedipine cream (0.2% and 0.4%).
Evidence on the treatment of chronic vulvodynia using gabapentin and nifedipine was very limited. One SR43 included 4 before-after studies of topical gabapentin and 1 RCT of nifedipine compared with placebo were included in this report. Because a placebo control was lacking in the studies included in the SR,43 the evidence only suggests a correlation between the use of topical gabapentin and the improvement in pain scores. The main limitation of the before-after studies is the inability to prove causality.
The RCT40 had several limitations. First, the study size was small (10 patients per arm), and as such, the findings should only be considered exploratory, and conclusions could not be drawn regarding differences between outcome measures. Second, the study was limited to a population of young women (mean age 25 years), and as such, the findings may not be generalizable to older populations. Third, it was unclear why the study only included patients with vulvodynia for at least 6 months, and the study did not investigate the association between the duration of vulvodynia and treatment outcome. Fourth, because the condition of vulvodynia is likely multifactorial, the study did not investigate whether nifedipine therapy may benefit patients with certain characteristics (e.g., type of vulvodynia [primary or secondary], women with dysuria versus those without).
One RCT41 provided evidence on topical nifedipine for treatment of pressure ulcers. The risks of bias of the included studies are presented first, followed by a description of the summary of findings.
Table 15 in this report presents the summary results of the risk-of-bias assessment of the included primary study41 examining nifedipine. We used RoB 2 to assess the risk of bias of the RCT. Overall, the included double-blind RCT41 had a low risk of bias.
Table 16 in this report presents the main characteristics and key findings of the study evaluating topical nifedipine for chronic pressure ulcers. Table 50 in Appendix 5 of the Supplemental Material document presents more details of the findings.
The RCT by Zolfagharnezhad et al.41 investigated the effect of topical nifedipine 3% ointment compared to placebo in critically ill patients with stage 1 or 2 pressure ulcers for 2 weeks.
Topical nifedipine 3% ointment may result in a decrease in pressure ulcer pain intensity (demonstrated by change in stage) or in pressure ulcer size compared to placebo.
No local AEs were observed.
Evidence on the treatment of pressure ulcers by topical nifedipine was from 1 placebo-controlled RCT41 of low risk of bias. The study had some limitations. First, the majority of patients were male (75%), which limits the generalizability of the findings to female patients. Second, wounds were evaluated by visual inspection and a validated observational scale. More objective approaches using sophisticated instruments such as imaging modalities were not used to precisely evaluate the wound bed and surrounding tissues. Third, the funding source was not reported.
Acute musculoskeletal pain: One SR45 and 9 RCTs22-24,55-60 of 2 drugs (i.e., ketoprofen and diclofenac) provided evidence regarding the treatment of acute musculoskeletal pain, usually from sport injuries, in adolescents and adults. The risk of bias of the included studies is presented first, followed by a description of the summary of findings.
Table 17 in this report presents the results of quality and bias assessment of the studies included in the SR45 for acute musculoskeletal pain. The assessments were conducted by the authors of the SR.45
The SR by Wiffen and Xia45 included 23 RCTs examining diclofenac. The authors of the SR45 used RoB 1 to assess the risk of bias of the RCTs. Briefly, 1 study had a high risk of bias for incomplete outcome data (attrition bias). The majority had some concerns (unclear risk of bias) or low risk of bias for other items.
Table 18 in this report presents the summary results of the risk-of-bias assessment of the included 3 RCTs22-24 examining ketoprofen and 6 RCTs55-60 examining diclofenac. We used RoB 2 to assess the risk of bias of the RCTs.
All 3 RCTs22-24 examining the use of ketoprofen had some concerns (unclear risk of bias) for randomization because the randomization process was not described, although they were all double-blind RCTs.
Of the 6 RCTs examining diclofenac, 156 had a high risk of bias, 258,60 had some concerns (unclear risk of bias), and 355,57,59 demonstrated a low risk of bias.
Table 19 in this report presents the main characteristics and key findings of the studies evaluating topical ketoprofen and topical diclofenac for acute musculoskeletal pain. Table 51, Table 52, and Table 53 in Appendix 5 of the Supplemental Material document present more details of the findings.
Three RCTs22-24 of ketoprofen were included.
Key findings:
The RCT by Serinken et al. (2020)24 found that children and adolescents aged 7 to 18 years receiving ketoprofen 2.5% gel for treatment of ankle sprain in emergency departments experienced an immediate reduction in pain intensity after 15 minutes and 30 minutes compared to placebo. There were no differences in the use of rescue drugs for pain relief between groups, and no AEs were reported in either group.
In another RCT by Serinken et al. (2016),23 similar observations were found for adults treated with ketoprofen 2.5% gel for ankle sprain in an emergency department setting.
In the RCT by Seidel et al.,22 there was no evidence of a difference between topical ketoprofen (100 mg) in transferosome gel and placebo, or between topical ketoprofen (200 mg) in transferosome gel and placebo for the reduction of muscle soreness following exercise, recovery time to muscle soreness, or the proportion of patients who had no pain at the end of the study. Treatment-related AEs and application site erythema were more frequent with the use of 200 mg ketoprofen gel. No serious AEs were observed.
One RCT22 comparing the efficacy of topical ketoprofen in transferosome gel with oral ketoprofen was included.
Key findings:
In the RCT by Seidel et al.,22 there was no evidence of a difference between topical ketoprofen in transferosome gel of both concentrations (100 mg or 200 mg) and oral ketoprofen (100 mg) for the reduction of muscle soreness following exercise.
The SR by Wiffen and Xia45 compared the efficacy of topical diclofenac (patch [with or without heparin], gel [1%, 2.32%], spray gel [4%]) with placebo for the treatment of sprains, strains, or contusions, primarily in patients with sport-related injuries.
Key findings:
Topical diclofenac may be a successful treatment (defined as at least a 50% reduction in pain) for acute musculoskeletal pain from sport-related injuries compared to placebo. The NNT was 3.7, meaning that for every 4 patients treated with topical diclofenac, 1 will experience successful treatment who would not have done so with placebo.
There was no evidence of a difference between groups for local AEs (redness or erythema, and itch or pruritus), systemic AEs, or withdrawal due to AEs.
Five RCTs55,56,58-60 examining the use of topical diclofenac were included.
Key findings:
The RCT by Pabst et al.55 found that both 140 mg diclofenac sodium plaster and 180 mg diclofenac epolamine plaster may be more effective in relieving pain in patients with limb injuries or contusions compared to placebo. Common AEs were mostly skin reactions at the application site (irritation, erythema, itching, burning), and withdrawal due to AEs was similar in all groups.
The RCT by Bukhari et al.56 compared topical diclofenac gel of different concentrations and formulations with placebo for treatment of sport injuries. The gels were applied with or without phonophoresis (ultrasound). The authors of the RCTs reported the results in the form of graphs and P values. All topical diclofenac gel forms appeared to be more effective than placebo in improving pain, stiffness, and physical function. AEs were not reported.
The RCT by Predel et al. (2020)58 found that there was no evidence of a difference in pain reduction between topical diclofenac 2% gel and placebo for the treatment of acute back or neck pain. Similar findings were observed in the comparison between topical diclofenac gel with capsaicin gel and capsaicin gel alone. Skin AEs such as burning sensation and skin and subcutaneous disorders appeared to be associated with capsaicin gel.
The RCT by Lai et al.59 found that there was no evidence of a difference in pain, swelling, and response to treatment among topical diclofenac 1% gel, placebo gel, diclofenac 1% with menthol 3% gel, and menthol 3% gel in the treatment of pain associated with ankle sprains. Diclofenac 1% gel with menthol 3% gel may be associated with a higher incidence of skin AEs and application site AEs than placebo or diclofenac 1% gel.
The RCT by Predel et al. (2016)60 found that the use of topical diclofenac patches (140 mg) may result in pain reduction in the treatment of soft tissue injuries of the limbs from sport injuries compared to placebo. Similar results were found for pain on movement and at rest, pain on pressure, time to efficacy onset, and global patient and investigator efficacy assessment. Local AEs at the application site appeared to be comparable between groups.
Two RCTs56,57 examining the effects of different concentrations of topical diclofenac were included.
Key findings:
The RCT by Bukhari et al.56 found that topical diclofenac gel of different concentrations may improve pain, stiffness, and physical function in a dose-dependent manner when treating sports injuries.
The RCT by Yin et al.7 found that there is no evidence of a difference between diclofenac diethylamine 1.16% gel applied 4 times per day and diclofenac diethylamine 2.32% gel applied 2 times per day for pain reduction and relief in the treatment of ankle sprains. Similar trends were seen for other outcomes such as ankle tenderness, joint function, and swelling. All treatment-related AEs were dermatological and appeared to be comparable between groups.
Three RCTs22-24 provided evidence on topical ketoprofen for the treatment of acute musculoskeletal pain (e.g., ankle sprain or muscle soreness following exercise). Although all the RCTs had a low risk of bias in general, except for the randomization process, they had several limitations. First, the studies had relatively small sample sizes, meaning that the findings were prone to random error. Second, treatment duration was short. Patients in 2 studies23,24 were treated with topical ketoprofen after presenting with ankle sprain at the emergency department, followed by assessment of pain intensity at 15 minutes and 30 minutes after treatment. The treatment duration of participants included in the third RCT22 was 1 week. As such, the RCTs did not provide data for longer-term efficacy of topical ketoprofen for acute musculoskeletal pain.
Evidence of topical diclofenac for the treatment of acute musculoskeletal pain was derived from 1 SR45 and 6 RCTs.55-60 The methodological quality of studies included in the SR45 was mixed, with 4 included studies including a relatively small sample size (fewer than 50 patients per arm). The treatment duration of the included studies was relatively short (most studies lasted for 7 to 14 days).
The RCTs55-60 examining topical diclofenac for the treatment of acute musculoskeletal pain had several limitations. First, the treatment duration was short, varying from 5 days to 4 weeks. Second, the findings of the RCT by Bukhari et al.56 should be interpreted with extra care, given that the study was small (20 patients in each arm), had a high risk of bias, and presented the results in the form of graphs and P values only. Third, most studies were sponsored by manufacturers that may be vulnerable to funding bias, although there was no clear evidence of design bias, outcome reporting bias, or selection of reported result bias. Fourth, differences in formulations, concentrations, doses, patient characteristics, severity of the injuries, location of injuries, and treatment duration may contribute to the heterogeneity of the results.
Of the 3 included RCTs, 131 examining topical clonidine and 261,62 examining topical diclofenac provided evidence for the treatment of cancer-related pain or conditions in adults with cancer. The risk of bias of the included studies is presented first, followed by a description of the summary of findings.
Table 20 in this report presents the summary results of the risk of bias assessment of the included RCTs.31,61,62 We used RoB 2 to assess the risk of bias of the RCTs. Overall, all the included RCTs demonstrated a low risk of bias for all items of RoB 2.
Table 21 in this report presents the key findings of the studies evaluating topical clonidine and topical diclofenac for treating cancer-related pain or conditions. Table 54 and Table 55 in Appendix 5 of the Supplemental Material document present more details of the findings.
The RCT by Giralt et al.31 found that treatment with topical clonidine mucobuccal tablets at either concentration (50 mcg or 100 mcg) may result in little to no difference compared to placebo in the prevention of severe oral mucositis in patients who underwent chemoradiation for the treatment of head and neck cancer. The same findings were observed for all other outcomes. Patients in both topical clonidine groups may have lower incidence of nausea, dysphagia, vomiting, weight loss, and oral fungal infection compared to those in the placebo group.
The RCT by Giralt et al.31 showed no evidence of a difference between 2 concentrations of topical clonidine mucobuccal tablet (50 mcg versus 100 mcg) for the prevention of chemoradiation-induced severe oral mucositis.
The RCT by Santhosh et al.61 found that the use of topical diclofenac 1% gel may result in better prevention of capecitabine-induced HFS (grade 1 to 3) in patients with breast or GI cancer compared to placebo. Topical diclofenac may result in a lower frequency of capecitabine dose reduction due to HFS compared to placebo. There was no difference in total AEs between groups. Common AEs in both groups were diarrhea and mucositis. No cardiovascular AEs were observed.
The RCT by Yamaguchi et al.62 found that the use of topical diclofenac patches from 150 mg/day to 225 mg/day may result in a longer analgesic effect compared to placebo (i.e., longer time to insufficient analgesic response). Likewise, topical diclofenac patches may result in better improvement in pain relief, sleep quality, and patient satisfaction. The incidences of AEs were comparable in both groups.
One RCT by Giralt et al.31 that had a low risk of bias provided evidence for the use of topical clonidine in the form of mucoadhesive buccal tablets for the relief of oral mucositis in patients who underwent chemoradiation therapy for head and neck cancer. The RCT had some limitations. First, although the sample size was calculated, the study may be underpowered, leading to the lack of statistical significance associated with the efficacy of the primary outcome. Second, the study was sponsored by a manufacturer, which may contribute to an interpretive bias. Third, the population consisted of mostly white (95%) and male (75%) patients, which may limit the generalizability of the findings to other populations. Thus, differences in terms of age, sex, ethnicity, tumour location, doses of radiation therapy, and doses of chemotherapy may contribute to the heterogeneity of the results.
One RCT by Santhosh et al.61 that had a low risk of bias provided evidence for the use of topical diclofenac for the prevention of capecitabine-associated HFS. The study had some limitations. First, diclofenac application was limited to the hands in this study; thus, the effect of topical diclofenac when applied to the foot was unclear. Second, the study received funding from the manufacturer, making it vulnerable to funding bias, including data manipulation and interpretive bias. Third, there were more females (71%) than males in the study population, which may restrict the generalizability to the male population. Differences in study characteristics in terms of sex, performance status (mostly Eastern Cooperative Oncology Group performance status 0 and 1), type of therapy (mono versus combo), type of cancer (breast versus GI), previous chemotherapy, and stage of cancer may contribute to the heterogeneity of the results.
One RCT by Yamaguchi et al.62 that had a low risk of bias provided positive evidence for the use of topical diclofenac for the treatment of patients with cancer pain. The study appeared to have no apparent limitations, except that it was sponsored by a manufacturer, which may make it vulnerable to funding bias. Differences in study characteristics in terms of type of cancer, location of cancer, stage of cancer, Eastern Cooperative Oncology Group performance status, and assessment site may contribute to the heterogeneity of the results.
This review included 36 publications, comprised of 7 SRs19-21,30,43-45 and 29 RCTs22-24,28,31,35-41,46-62 evaluating the clinical efficacy and safety of 7 topical drugs (i.e., ketamine, ketoprofen, baclofen, clonidine, nifedipine, gabapentin, and diclofenac) for the treatment of pain associated with osteoarthritis, chronic musculoskeletal pain, acute musculoskeletal pain, neuropathy, anal fissures, vulvodynia, pressure ulcers, and cancer.
Evidence for the efficacy and safety of topical ketoprofen in the treatment of pain associated with knee osteoarthritis came from 2 SRs,20,21 which included 2 RCTs and 4 RCTs, respectively. Compared to the carrier transferosome gel alone as placebo, ketoprofen gel showed little to no difference in pain relief and improvement in physical function. Despite mild or moderate AEs, topical ketoprofen appeared to be associated with increases in local AEs (e.g., skin and soft tissue disorders) and no differences with respect to systemic AEs (e.g., GI or cardiovascular disorders) compared to placebo.
Four SRs20,21,44,45 with meta-analysis and 6 RCTs46-51 provided evidence for the efficacy and safety of topical diclofenac in the treatment of osteoarthritis of the knee or hand compared with placebo. Of the included studies, 1 SR45 compared the efficacy and safety of topical diclofenac with oral diclofenac tablet, and 1 RCT51 compared the efficacy and safety of 2 different concentrations of topical diclofenac.
Topical diclofenac of different formulations, carriers, and concentrations appeared to be more effective than placebo for pain relief and improvement in physical function and stiffness in all periods up to 12 weeks of treatment. The benefits of topical diclofenac appeared to be dose-dependent with minimal AEs. Both topical and oral formulations of diclofenac appeared to provide similar levels of pain relief, with more local AEs (skin disorders) associated with topical diclofenac, whereas systemic AEs (GI disorders) were associated with oral diclofenac.
Evidence for the clinical efficacy and safety of topical diclofenac for the treatment of chronic musculoskeletal pain was derived from 3 RCTs.52-54 Compared to placebo, both topical diclofenac patches (75 mg and 150 mg) were equally effective for the control of low back pain in adults. Topical diclofenac patches may be as effective as oral diclofenac sustained-release tablets in patients with chronic musculoskeletal pain, including patients with low back pain. However, topical diclofenac patches were associated with a lower risk of GI disorders compared to oral diclofenac tablets.
One SR19 evaluated the benefits and harms of topical ketamine for adults with chronic neuropathic pain. An analysis of the 3 included RCTs showed that there was inconclusive evidence that topical ketamine reduces pain intensity at the immediate- or short-term follow-up compared to placebo.
One RCT28 with high risk of bias showed inconclusive evidence that topical baclofen reduces pain intensity during short-term treatment compared to placebo. AEs were not observed.
One SR30 found no evidence that topical clonidine was better than placebo for patient-reported neuropathic pain relief of 50% or greater during the 12-week treatment period. However, more patients may achieve pain relief of at least 30% when treated with topical clonidine compared to those treated with placebo. Tolerability was similar between groups.
Five RCTs35-39 with high risk of bias provided evidence regarding the efficacy and safety of topical nifedipine compared with placebo or oral nifedipine tablets in the treatment of chronic anal fissures.
Compared to conservative treatment, the addition of topical nifedipine to conservative treatment may result in better pain relief and may achieve a better rate of ulcer healing. There was no clear evidence of a difference between topical nifedipine and oral nifedipine in pain relief or ulcer healing. AEs were minimal and similar in all treatment groups.
Evidence from an SR43 of 4 before-after studies could only provide a correlation between the use of topical gabapentin and the improvement in pain scores. The lack of a placebo-controlled arm in the included studies of the SR could not preclude the placebo effect of the gabapentin formulations. Thus, a conclusion could not be made due to inherent limitations of the included studies.
Evidence from 1 RCT40 showed that both topical nifedipine and placebo reduced pain in women with vulvodynia, and the effectiveness of topical nifedipine at both low and high concentrations did not exceed that of placebo. Topical AEs were mild and ceased with continued treatment of topical nifedipine. Thus, a strong placebo effect of the ointment itself in treatment of vulvodynia could not be ruled out.
Evidence from 1 RCT41 with a low risk of bias showed that topical nifedipine may improve the healing process of stage 1 or 2 pressure ulcers in critically ill patients. Local AEs were not detected.
Evidence from 2 RCTs23,24 suggested that ketoprofen gel was superior to placebo in immediate reduction in pain intensity from ankle sprains in children and adults in an emergency setting. One RCT22 showed a strong placebo effect of transferosome gel at both concentrations (100 mg, 200 mg) and that topical ketoprofen in transferosome gel was not superior to transferosome gel alone for the reduction of muscle soreness following exercise. Also, no evidence was found comparing topical ketoprofen and oral ketoprofen for the treatment of muscle soreness following exercise. AEs were minimal, and no serious AEs were reported in any treatment groups.
Evidence from 1 SR45 and 3 RCTs55,56,60 suggested that topical diclofenac of different concentrations and formulations was effective for acute musculoskeletal pain, with minimal AEs. However, combinations of diclofenac gel with capsaicin58 or diclofenac gel with 3% menthol59 were not more effective than capsaicin gel or menthol gel alone. The effect of topical diclofenac may or may not be dose-dependent.56,57 AEs were generally minor in nature and few in number.
Evidence from 1 RCT31 with a low risk of bias could not provide a definitive conclusion as to whether topical clonidine can mitigate chemoradiotherapy-associated mucositis compared to placebo. AEs were rare and appeared to occur less frequently in the group treated with clonidine.
Evidence from 1 RCT61 with a low risk of bias demonstrated that topical diclofenac gel application is associated with a lower rate of HFS, lower rate of capecitabine dose reduction, and better QoL compared to placebo. Total AEs were similar in both groups.
Evidence from 1 RCT62 with a low risk of bias showed that topical diclofenac patches were effective in treating cancer pain and were well tolerated compared to placebo.
Overall, the evidence is limited by small sample sizes and the mostly high risk of bias with low certainty. This highlights the need for larger, well-designed clinical trials.
Most of the studies included in this review had short follow-up periods. Future studies should include long-term data to assess durability of results and long-term safety, especially for chronic pain conditions.
Future studies should include health-related QoL and patient-reported outcomes.
Multicentre studies are needed to confirm the results of single studies or results based on limited evidence (e.g., diclofenac for cancer pain or cancer-related conditions, clonidine for relieving oral mucositis, nifedipine for pressure ulcers and vulvodynia, gabapentin for vulvodynia, and baclofen for neuropathic pain).
The quality and certainty of evidence varied across topical agents, and therefore, treatment decisions should be based on the specific drug and indication, rather than generalized across all topical agents.
Topical diclofenac has the most consistent evidence for use in patients with osteoarthritis and chronic or acute musculoskeletal pain. The evidence of the use of topical diclofenac for cancer pain and prevention of capecitabine-associated HFS is promising but not conclusive.
Current evidence is insufficient to support the use of topical ketamine, clonidine, and baclofen for treatment of neuropathic pain; topical clonidine for improvement of chemoradiotherapy-associated mucositis; topical gabapentin and nifedipine for vulvodynia; and topical ketoprofen for knee osteoarthritis, because of the low to very low certainty of the evidence.
Topical nifedipine may offer clinical benefits for chronic anal fissures and early-stage pressure ulcers; however, confidence in these findings is limited.
Overall, AEs were mild and localized for most topical drugs, suggesting a favourable safety profile.
Clinicians and policy-makers should interpret findings cautiously and consider patient values and preferences, treatment goals, and available alternative treatments in addition to the evidence in this review.
1.Pain. 2026. Accessed 24 June. https://www.ninds.nih.gov/health-information/disorders/pain
2.Chronic pain. 2024. Accessed 24 June. https://my.clevelandclinic.org/health/diseases/4798-chronic-pain
3.Causes and types of cancer pain. 2024. Accessed 24 June. https://www.cancerresearchuk.org/about-cancer/coping/physically/cancer-and-pain-control/causes-and-types
4.Choi E, Nahm FS, Han WK, Lee PB, Jo J. Topical agents: a thoughtful choice for multimodal analgesia. Korean J Anesthesiol. 2020;73(5):384-393. doi:10.4097/kja.20357 PubMed
5.Taira T, Kawamura H, Tanikawa T, Iseki H, Kawabatake H, Takakura K. A new approach to control central deafferentation pain: spinal intrathecal baclofen. Stereotact Funct Neurosurg. 1995;65(1-4):101-5. doi:10.1159/000098905 PubMed
6.Giovannitti JA, Jr., Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. 2015;62(1):31-9. doi:10.2344/0003-3006-62.1.31 PubMed
7.Romero-Sandoval A, Eisenach JC. Clonidine reduces hypersensitivity and alters the balance of pro- and anti-inflammatory leukocytes after local injection at the site of inflammatory neuritis. Brain Behav Immun. 2007;21(5):569-80. doi:10.1016/j.bbi.2006.09.001 PubMed
8.Diclofenac. 2026. Accessed 03 June. https://www.mayoclinic.org/drugs-supplements/diclofenac-oral-route/description/drg-20069748
9.Gabapentin. 2021. Accessed 03 June. https://my.clevelandclinic.org/health/drugs/21561-gabapentin
10.Ketamine for Chronic Pain: What You Need to Know. 2026. Accessed 25 June. https://unikamed.com/ketamine-for-pain-what-to-know/
11.Ketamine Therapy for Pain Management: A Revolutionary Approach to Chronic Pain Relief. 2026. Accessed 03 June. https://unikamed.com/ketamine-therapy-for-pain-management-a-revolutionary-approach-to-chronic-pain-relief/
12.Sarzi-Puttini P, Atzeni F, Lanata L, et al. Pain and ketoprofen: what is its role in clinical practice? Reumatismo. 2010;62(3):172-88. doi:10.4081/reumatismo.2010.172 PubMed
13.Nifedipine. 2025. Accessed 03 June. https://www.ncbi.nlm.nih.gov/books/NBK537052/
14.Magni A, Agostoni P, Bonezzi C, et al. Management of Osteoarthritis: Expert Opinion on NSAIDs. Pain Ther. 2021;10(2):783-808. doi:10.1007/s40122-021-00260-1 PubMed
15.Stanos SP. Topical agents for the management of musculoskeletal pain. J Pain Symptom Manage. 2007;33(3):342-55. doi:10.1016/j.jpainsymman.2006.11.005 PubMed
16.Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. doi:10.1136/bmj.j4008 PubMed
17.RoB2 Development Group. PT Higgins JPT, Savović J, Page MJ, Sterne JAC, eds. Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). 2019. Accessed January 1, 1800. https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/current-version-of-rob-2
18.Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-e34. doi:10.1016/j.jclinepi.2009.06.006 PubMed
19.Ferraro MC, Cashin AG, Visser EJ, et al. Ketamine and other NMDA receptor antagonists for chronic pain. Cochrane Database Syst Rev. 2025;8:CD015373. doi:10.1002/14651858.CD015373.pub2 PubMed
20.Wolff DG, Christophersen C, Brown SM, Mulcahey MK. Topical nonsteroidal anti-inflammatory drugs in the treatment of knee osteoarthritis: a systematic review and meta-analysis. Physician & Sportsmedicine. 2021;49(4):381-391. doi:10.1080/00913847.2021.1886573 PubMed
21.Honvo G, Leclercq V, Geerinck A, et al. Safety of Topical Non-steroidal Anti-Inflammatory Drugs in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis. Drugs Aging. 2019;36(Suppl 1):45-64. doi:10.1007/s40266-019-00661-0 PubMed
22.Seidel EJ, Rother M, Regenspurger K, Rother I. A randomised trial comparing the efficacy and safety of topical ketoprofen in Transfersome(R) gel (IDEA-033) with oral ketoprofen and drug-free ultra-deformable Sequessome TM vesicles (TDT 064) for the treatment of muscle soreness following exercise. J Sports Sci. 2016;34(1):88-95. doi:10.1080/02640414.2015.1035667 PubMed
23.Serinken M, Eken C, Elicabuk H. Topical Ketoprofen Versus Placebo in Treatment of Acute Ankle Sprain in the Emergency Department. Foot Ankle Int. 2016;37(9):989-93. doi:10.1177/1071100716650530 PubMed
24.Serinken M, Eken C, Tunay K, Golcuk Y. Topical Ketoprofen Versus Placebo in Children Presenting With Ankle Sprain to the Emergency Department: A Randomized Controlled Study. Pediatr Emerg Care. 2020;36(8):e447-e450. doi:10.1097/pec.0000000000001595 PubMed
25.Bahreini M, Safaie A, Mirfazaelian H, Jalili M. How much change in pain score does really matter to patients? Am J Emerg Med. 2020;38(8):1641-1646. doi:10.1016/j.ajem.2019.158489 PubMed
26.Reed DE, 2nd, Stump TE, Monahan PO, Kroenke K. Comparable Minimally Important Differences and Responsiveness of Brief Pain Inventory and PEG Pain Scales across 6 Trials. J Pain. 2024;25(1):142-152. doi:10.1016/j.jpain.2023.07.028 PubMed
27.Todd KH, Funk JP. The minimum clinically important difference in physician-assigned visual analog pain scores. Acad Emerg Med. 1996;3(2):142-6. doi:10.1111/j.1553-2712.1996.tb03402.x PubMed
28.Ala S, Enayatifard R, Monajati M, et al. The Analgesic Effects of Baclofen 5% Topical Cream for Treatment of Diabetic Peripheral Neuropathy: a Placebo-Control and Double-Blinded Clinical Trial. SN Comprehensive Clinical Medicine. 2022;4(1) (no pagination). doi:10.1007/s42399-021-01108-7
29.DN4 questionnaire. 2026. Accessed 02 June. https://www.physio-pedia.com/DN4_questionnaire
30.Serednicki WT, Wrzosek A, Woron J, et al. Topical clonidine for neuropathic pain in adults. Cochrane Database Syst Rev. 2022;5:CD010967. doi:10.1002/14651858.CD010967.pub3 PubMed
31.Giralt J, Tao Y, Kortmann RD, et al. Randomized Phase 2 Trial of a Novel Clonidine Mucoadhesive Buccal Tablet for the Amelioration of Oral Mucositis in Patients Treated With Concomitant Chemoradiation Therapy for Head and Neck Cancer. Int J Radiat Oncol Biol Phys. 2020;106(2):320-328. doi:10.1016/j.ijrobp.2019.10.023 PubMed
32.Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on subjective outcome measures. J Manipulative Physiol Ther. 2004;27(1):26-35. doi:10.1016/j.jmpt.2003.11.003 PubMed
33.Ceniza-Bordallo G, Li R, de la Vega R, Palermo TM. Patient global impression of change in pediatric chronic pain clinical trials: A review and secondary analysis of randomized controlled trial data. J Pain. 2026:106312. doi:10.1016/j.jpain.2026.106312 PubMed
34.Stiff PJ, Erder H, Bensinger WI, et al. Reliability and validity of a patient self-administered daily questionnaire to assess impact of oral mucositis (OM) on pain and daily functioning in patients undergoing autologous hematopoietic stem cell transplantation (HSCT). Bone Marrow Transplant. 2006;37(4):393-401. doi:10.1038/sj.bmt.1705250 PubMed
35.Agrawal V, Kaushal G, Gupta R. Randomized controlled pilot trial of nifedipine as oral therapy vs. topical application in the treatment of fissure-in-ano. Am J Surg. 2013;206(5):748-51. doi:10.1016/j.amjsurg.2013.05.003 PubMed
36.Bhatia AS. Comparison of Effectiveness of Topical Versus Oral Nifedipine for Treatment of Chronic Anal Fissure. International Journal of Life Sciences Biotechnology and Pharma Research. 2025;14(7):1885-1887. doi:10.69605/ijlbpr_14.7.2025.320
37.Golfam F, Golfam P, Khalaj A, Sayed Mortaz SS. The effect of topical nifedipine in treatment of chronic anal fissure. Acta Med Iran. 2010;48(5):295-9. PubMed
38.Golfam F, Golfam P, Golfam B, Pahlevani P. Comparison of topical nifedipine with oral nifedipine for treatment of anal fissure: a randomized controlled trial. Iran. 2014;16(8):e13592. doi:10.5812/ircmj.13592
39.Sinha A, Kumar A. Prospective Randomized Controlled Study of Nifedipine as Oral Therapy vs Topical Application in the Management of Anal Fissure. International Journal of Toxicological and Pharmacological Research. 2024;14(5):144-146.
40.Bornstein J, Tuma R, Farajun Y, Azran A, Zarfati D. Topical nifedipine for the treatment of localized provoked vulvodynia: a placebo-controlled study. J Pain. 2010;11(12):1403-9. doi:10.1016/j.jpain.2010.03.016 PubMed
41.Zolfagharnezhad H, Khalili H, Mohammadi M, Niknam S, Vatanara A. Topical Nifedipine for the Treatment of Pressure Ulcer: A Randomized, Placebo-Controlled Clinical Trial. Am J Ther. 2021;28(1):e41-e51. doi:10.1097/mjt.0000000000000936 PubMed
42.Pedley GE. Comparison of pressure ulcer grading scales: a study of clinical utility and inter-rater reliability. Int J Nurs Stud. 2004;41(2):129-40. doi:10.1016/s0020-7489(03)00133-0 PubMed
43.Ergisi M, Law A, Chaudhari N, Tsatsari S, Lawson K, Jenner C. Effectiveness of topical gabapentin in the treatment of vulvodynia: a narrative synthesis. Frontiers in Pain Research. 2023;4:1159268. doi:10.3389/fpain.2023.1159268 PubMed
44.Chen ZR, Chen BK, Li P, Feng K. Efficacy and safety of different topical diclofenac formulations for the treatment of knee osteoarthritis: a meta-analysis of short-term and long-term treatment comparisons. BMC Musculoskelet Disord. 2025;26(1):230. doi:10.1186/s12891-025-08465-7 PubMed
45.Wiffen PJ, Xia J. Systematic review of topical diclofenac for the treatment of acute and chronic musculoskeletal pain. Curr Med Res Opin. 2020;36(4):637-650. doi:10.1080/03007995.2020.1716703 PubMed
46.Abbasifard M, Moosavi Z, Azimi M, et al. Effect of Topical Hemp (Cannabis sativa L.) Seed Oil on Knee Osteoarthritis: A Randomized Double-Blind Controlled Trial. Pain Manag Nurs. 2025;26(1):e74-e81. doi:10.1016/j.pmn.2024.08.001 PubMed
47.Bhatia A, Goni V, Chopra S, Singh B, Katare OP. Evaluation of efficacy and safety of a novel lipogel containing diclofenac: A randomized, placebo controlled, double-blind clinical trial in patients with signs and symptoms of osteoarthritis. Contemporary Clinical Trials Communications. 2020;20:100664. doi:10.1016/j.conctc.2020.100664 PubMed
48.Li T, Guo M, Zhang W. Comparison of Therapeutic Effects of Topical Application of Diclofenac Sodium Nanoparticles and Conventional Placebo on Knee Osteoarthritis. Cell Mol Biol. 2022;68(3):171-178. doi:10.14715/cmb/2022.68.3.20 PubMed
49.Dehghan M, Asgharian S, Khalesi E, Ahmadi A, Lorigooini Z. Comparative study of the effect of Thymus daenensis gel 5% and diclofenac in patients with knee osteoarthritis. Biomedicine. 2019;9(2):9. doi:10.1051/bmdcn/2019090209 PubMed
50.Dehghan M, Saffari M, Rafieian-kopaei M, Ahmadi A, Lorigooini Z. Comparison of the effect of topical Hedera helix L. extract gel to diclofenac gel in the treatment of knee osteoarthritis. Journal of Herbal Medicine. 2020;22(no pagination). doi:10.1016/j.hermed.2020.100350
51.Tolu S, Kose MM, Korkmaz MC, Usen A, Rezvani A. Comparison of the Efficacy of Different Concentrations of Diclofenac Sodium Phonophoresis (1.16% vs 2.32%) in Patients with Knee Osteoarthritis: a Randomized Double-Blind Controlled Trial. Acta Chir Orthop Traumatol Cech. 2021;88(2):117-123. PubMed
52.Fukase H, Futagami S, Yamamoto T, et al. Investigation of the effects of a new transdermal formulation of systemic diclofenac on the upper gastrointestinal mucosa in patients with low back pain: A comparative study with oral diclofenac. J Gastroenterol Hepatol. 2024;39(12):2504-2510. doi:10.1111/jgh.16810 PubMed
53.Taguchi T, Yamaguchi S, Terahara T, Okawa K, Inakura H. Systemically Acting Diclofenac Sodium Patch for Control of Low Back Pain: A Randomized, Double-Blind, Placebo-Controlled Study in Japan. Pain Ther. 2023;12(2):529-542. doi:10.1007/s40122-023-00478-1 PubMed
54.Shinde VA, Kalikar M, Jagtap S, et al. Efficacy and Safety of Oral Diclofenac Sustained release Versus Transdermal Diclofenac Patch in Chronic Musculoskeletal Pain: A Randomized, Open Label Trial. Journal of Pharmacology and Pharmacotherapeutics. 2017;8(4):166-171. doi:10.4103/jpp.JPP_35_17 PubMed
55.Pabst H, Gruber G, Picciotto R, Barbaro B, Giordan N. Efficacy and safety of Diclofenac sodium plaster in patients with acute pain of the limbs: a randomized, placebo and active-controlled, double-blind, parallel-group trial. Eur Rev Med Pharmacol Sci. 2023;27(7):3181-3190. doi:10.26355/eurrev_202304_31952 PubMed
56.Bukhari KA, Khan IA, Ishaq S, et al. Formulation and Evaluation of Diclofenac Potassium Gel in Sports Injuries with and without Phonophoresis. Gels. 2022;8(10):26. doi:10.3390/gels8100612 PubMed
57.Yin F, Ma J, Xiao H, et al. Randomized, double-blind, noninferiority study of diclofenac diethylamine 2.32% gel applied twice daily versus diclofenac diethylamine 1.16% gel applied four times daily in patients with acute ankle sprain. BMC Musculoskelet Disord. 2022;23(1):1125. doi:10.1186/s12891-022-06077-z PubMed
58.Predel HG, Ebel-Bitoun C, Peil B, Weiser TW, Lange R. Efficacy and Safety of Diclofenac + Capsaicin Gel in Patients with Acute Back/Neck Pain: A Multicenter Randomized Controlled Study. Pain Ther. 2020;9(1):279-296. doi:10.1007/s40122-020-00161-9 PubMed
59.Lai PM, Collaku A, Reed K. Efficacy and safety of topical diclofenac/menthol gel for ankle sprain: A randomized, double-blind, placebo- and active-controlled trial. J Int Med Res. 2017;45(2):647-661. doi:10.1177/0300060517700322 PubMed
60.Predel HG, Pabst H, Schafer A, Voss D, Giordan N. Diclofenac patch for the treatment of acute pain caused by soft tissue injuries of limbs: a randomized, placebo-controlled clinical trial. J Sports Med Phys Fitness. 2016;56(1-2):92-9. PubMed
61.Santhosh A, Sharma A, Bakhshi S, et al. Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial. J Clin Oncol. 2024;42(15):1821-1829. doi:10.1200/jco.23.01730 PubMed
62.Yamaguchi S, Terahara T, Okawa K, Inakura H. A multicenter, randomized, double-blind, placebo-controlled, comparative study to evaluate the efficacy and safety of newly developed diclofenac patches in patients with cancer pain. Pain. 2021;25:25. doi:10.1097/01.j.pain.0000831636.00436.22 PubMed
63.Challa DNV, Crowson CS, Davis JM, 3rd. The Patient Global Assessment of Disease Activity in Rheumatoid Arthritis: Identification of Underlying Latent Factors. Rheumatol Ther. 2017;4(1):201-208. doi:10.1007/s40744-017-0063-5 PubMed
64.WOMAC Osteoarthritis Index. 2026. Accessed 04 May https://www.physio-pedia.com/WOMAC_Osteoarthritis_Index
65.Clement ND, Bardgett M, Weir D, Holland J, Gerrand C, Deehan DJ. What is the Minimum Clinically Important Difference for the WOMAC Index After TKA? Clin Orthop Relat Res. 2018;476(10):2005-2014. doi:10.1097/corr.0000000000000444 PubMed
66.Hmamouchi I, Allali F, Tahiri L, et al. Clinically important improvement in the WOMAC and predictor factors for response to non-specific non-steroidal anti-inflammatory drugs in osteoarthritic patients: a prospective study. BMC Res Notes. 2012;5:58. doi:10.1186/1756-0500-5-58 PubMed
67.Smeets R, Köke A, Lin CW, Ferreira M, Demoulin C. Measures of function in low back pain/disorders: Low Back Pain Rating Scale (LBPRS), Oswestry Disability Index (ODI), Progressive Isoinertial Lifting Evaluation (PILE), Quebec Back Pain Disability Scale (QBPDS), and Roland-Morris Disability Questionnaire (RDQ). Arthritis Care Res (Hoboken). 2011;63 Suppl 11:S158-73. doi:10.1002/acr.20542 PubMed
68.Ostelo RW, de Vet HC. Clinically important outcomes in low back pain. Best Pract Res Clin Rheumatol. 2005;19(4):593-607. doi:10.1016/j.berh.2005.03.003 PubMed
69.Cohen SE, Zantvoord JB, Mattila TK, Storosum BWC, de Boer A, Denys D. The minimal important difference in obsessive-compulsive disorder: An analysis of double-blind SSRI trials in adults. Eur Psychiatry. 2024;67(1):e53. doi:10.1192/j.eurpsy.2024.1768 PubMed
70.Fischer AA. Pressure algometry over normal muscles. Standard values, validity and reproducibility of pressure threshold. Pain. 1987;30(1):115-126. doi:10.1016/0304-3959(87)90089-3 PubMed
71.Fares A, Picot B, Lopes R, et al. Indicators of Return to Sports at Preinjury Levels Following Surgery for Chronic Ankle Instability: Comparison of ALR-RSI, AOFAS, and Karlsson Scores. Orthop J Sports Med. 2025;13(1):23259671241302078. doi:10.1177/23259671241302078 PubMed
72.Tatro-Adams D, McGann SF, Carbone W. Reliability of the figure-of-eight method of ankle measurement. J Orthop Sports Phys Ther. 1995;22(4):161-3. doi:10.2519/jospt.1995.22.4.161 PubMed
73.Bernstein SL, Bijur PE, Gallagher EJ. Relationship between intensity and relief in patients with acute severe pain. Am J Emerg Med. 2006;24(2):162-6. doi:10.1016/j.ajem.2005.08.007 PubMed
74.de Queiroz MVR, de Medeiros A, Toledo SP, de Abreu Sarmenghi KD, de Vasconcellos VF. Hand-foot syndrome caused by capecitabine: incidence, risk factors and the role of dermatological evaluation. Ecancermedicalscience. 2022;16:1390. doi:10.3332/ecancer.2022.1390 PubMed
75.Sibaud V, Dalenc F, Chevreau C, et al. HFS-14, a specific quality of life scale developed for patients suffering from hand-foot syndrome. Oncologist. 2011;16(10):1469-78. doi:10.1634/theoncologist.2011-0033 PubMed
76.Dougados M, Leclaire P, van der Heijde D, Bloch DA, Bellamy N, Altman RD. Response criteria for clinical trials on osteoarthritis of the knee and hip: a report of the Osteoarthritis Research Society International Standing Committee for Clinical Trials response criteria initiative. Osteoarthritis Cartilage. 2000;8(6):395-403. doi:10.1053/joca.2000.0361 PubMed
Please note that this appendix has not been copy-edited.
Table 2: Results of Quality and Bias Assessment of the Studies Included in the Systematic Reviews for Osteoarthritis
Study | Assessment tool | Description |
|---|---|---|
Wolff et al. (2021)20 | Jadad | Ketoprofen — 3 RCTs Diclofenac — 12 RCTs Ibuprofen — 3 RCTs
|
Honvo et al. (2019)21 | RoB 1 | Ketoprofen — 4 RCTs:
Diclofenac — 11 RCTs:
|
Chen et al. (2025)44 | RoB 2 | Diclofenac — 11 RCTs Most studies demonstrated a low risk of bias:
|
Wiffen and Xia (2020)45 | RoB 1 | Diclofenac — 21 RCTs:
|
RCT = randomized controlled trial; RoB 1 = original Cochrane risk-of-bias tool for randomized trials; RoB 2 = revised Cochrane risk-of-bias tool for randomized trials.
Table 3: Results of Quality and Bias Assessment of the Included Primary Studies for Osteoarthritis
Study | Randomization process | Deviations from intended interventions | Missing outcome data | Measurement of outcome | Selection of reported result | Overall |
|---|---|---|---|---|---|---|
Abbasifard et al. (2025)46 | Low | Low | Low | Low | Low | Low |
Bhatia et al. (2020)47 | Some concerns | Low | Low | Low | Low | Some concerns |
Li et al. (2022)48 | Some concerns | Some concerns | Low | High | Low | High |
Dehghan et al. (2019)49 | Low | Low | Low | Low | Low | Low |
Dehghan et al. (2020)50 | Low | Low | Low | Low | Low | Low |
Tolu et al. (2021)51 | Low | Low | Low | Low | Low | Low |
Percentages |
|
|
|
|
|
|
Table 4: Study Characteristics and Key Findings for Osteoarthritis
Reference (study type); Manufacturer’s sponsor | Target location | Topical treatment | Formulations (dose) | Comparator | Treatment duration | Efficacy | Safety |
|---|---|---|---|---|---|---|---|
Effect size (95% CI) OR Mean (SD) | |||||||
Wolff et al. (2021)20 (SR — 2 RCTs) NR | Knee | Ketoprofen | Transferosome gel (50 mg, 110 mg); 2 times per day | Placebo | 6 weeks, 12 weeks | SMD pain = 0.16 (−0.16 to 0.47) SMD physical function = 0.31 (0.19 to 0.42) | OR skin = 2.38 (1.21 to 4.70) OR GI = 0.70 (0.33 to 1.46) OR CV = 4.42 (0.56 to 35.29) |
Honvo et al. (2019)21 (SR — 4 RCTs) No | Knee | Ketoprofen | Transferosome gel (50 mg, 110 mg); 2 times per day | Placebo | 6 weeks to 12 weeks | NR | OR total AEs = 1.04 (0.90 to 1.20) OR withdrawal due to AEs = 1.37 (0.99 to 1.89) OR headache = 0.60 (0.41 to 0.88) OR GI = 0.78 (0.51 to 1.21) |
Wolff et al. (2021)20 (SR — 9 RCTs) NR | Knee | Diclofenac | Gel (1.16%, 2%); solution (1.5%); patch (180 mg); 2 to 4 times per day | Placebo | 2 weeks to 12 weeks | SMD pain = 0.34 (0.22 to 0.46) SMD physical function = 0.30 (0.23 to 0.37) | NR |
Honvo et al. (2019)21 (SR — 8 RCTs) No | Knee, hand | Diclofenac | Gel (1.16%, 2%); solution (1.5%); patch (180 mg); 2 to 4 times per day | Placebo | 2 weeks to 12 weeks | NR | OR total AEs = 1.30 (1.10 to 1.53) OR withdrawal due to AEs = 2.00 (1.27 to 3.14) OR skin = 1.73 (0.96 to 3.10) OR GI = 1.11 (0.75 to 1.64) CV disorders, musculoskeletal and connective tissue disorders, serious AEs, or severe AEs: NS |
Chen et al. (2025)44 (SR — 12 RCTs) No | Knee | Diclofenac | Gel (1.16%, 2%); solution (1.5%); patch (180 mg); 2 to 4 times per day | Placebo | 2 weeks to 12 weeks | At 8 to 12 weeks:
Similar results were seen for short-term (1 to 2 weeks) and medium term (3 to 8 weeks) treatment | Gel, solution or patch: NS for skin, GI, or withdrawal due to AEs |
Wiffen and Xia (2020)45 (SR — 18 RCTs) Yes | Knee, hand | Diclofenac | Gel (1%, 1.16%, 2%, 3%); solution (1.5%); patch (180 mg); 2 to 4 times per day | Placebo | 2 weeks to 12 weeks | RR Clinical successa = 1.2 (1.1 to 1.3) NNT Clinical successa = 9.5 (7 to 14.7) | Local AEs:
Withdrawal due to AEs:
Systemic AEs (headache, diarrhea, drowsiness and dyspepsia) or serious AEs: NR |
Wiffen and Xia (2020)45 (SR — 3 RCTs) Yes | Knee, hand | Diclofenac | Gel (1.16%); solution (1.5%); 3 to 4 times per day | Oral diclofenac (100 mg slow-release); 1 capsule daily — 2 RCTs Oral ibuprofen tablets (2 × 400 mg) 3 times daily — 1 RCT | 3 weeks to 12 weeks | RR response rate = 0.98 (0.89 to 1.08) | Local AEs
GI:
RR withdrawal due to AEs = 0.85 (0.68 to 1.1) RR withdraw due to lack of efficacy = 2.9 (1.64 to 5.16) Serious AEs: inconclusive due to too few events. |
Abbasifard et al. (2025)46 (RCT) No | Knee | Diclofenac | Gel (1%); 10 drops on knees before bedtime | Placebo | 8 weeks | Pain: 5.53 (1.83) vs. 9.10 (2.58); P = 0.001 Stiffness: 1.40 (0.86) vs. 2.17 (1.02); P = 0.001 Physical activity (hours per day): 21.23 (6.04) vs. 29.43 (6.75); P = 0.001 Heel-to-thigh distance, cm: 4.43 (0.45) vs. 3.55 (0.66); P = 0.53 |
|
Bhatia et al. (2020)47 (RCT) Yes | Knee | Diclofenac | Lipogel (20 g) Emulgel (20 g) Apply on knee 2 times per day | Placebo | 6 weeks | Pain:
Stiffness:
Physical function:
| No skin or GI AEs reported during the study period |
Li et al. (2022)48 (RCT) NR | Knee | Diclofenac | Nano flexible liposomes (0.5 to 1 g); 3 times per day | Placebo | 2 weeks | Pain: Significantly lower than control (P < 0.01) Swelling: 0.94 (0.59) vs. 1.93 (0.58); P < 0.05 Joint mobility disorder: 0.05 (0.42) vs. 1.82 (0.51); P < 0.05 |
|
Dehghan et al. (2019)49 (RCT) No | Knee | Diclofenac | Gel (1%); 3 times per day | Placebo | 6 weeks | Pain: 3.57 (0.41) vs. 10.35 (0.82); P = 0.000 Stiffness: 0.75 (0.09) vs. 2.1 (0.17); P = 0.000 Physical function: 12.58 (1.46) vs. 37.66 (2.92); P = 0.000 | Diclofenac: No topical or systemic AEs |
Dehghan et al. (2020)50 (RCT) No | Knee | Diclofenac | Gel (1%); 3 times daily; 3 times per day | Placebo | 6 weeks | Pain: 2.57 (1.08) vs. 2.7 (0.91); P = 0.63 Stiffness: 0.38 (0.57) vs. 0.81 (0.67); P = 0.006 Physical function: 26.43 (21.94) vs. 43.27 (19.01); P = 0.000 | NR |
Tolu et al. (2021)51 (RCT) NR | Knee | Diclofenac | DSPH gel (1.16%, 2.32%); 5 sessions per week | Placebo | 2 weeks | Pain:
Stiffness:
Physical function:
| No treatment-related AEs |
AE = adverse event; CI = confidence interval; CV = cardiovascular; DSPH = diclofenac sodium phonophoresis; GI = gastrointestinal; MD = mean difference; NNH = number needed to harm; NNT = number needed to treat; NR = not reported; NS = not statistically significant; OR = odds ratio; PGA = patient global assessment; RCT = randomized controlled trial; RR = relative risk; SD = standard deviation; SMD = standardized mean difference; SR = systematic review; vs. = versus.
aClinical success: At least a 50% reduction in pain intensity or an Osteoarthritis Research Society International Index (OARSI) response that includes response to pain, function, and patient’s global assessment.76
Table 5: Results of Quality and Bias Assessment of the Included Primary Studies for Chronic Musculoskeletal Pain
Study | Randomization process | Deviations from intended interventions | Missing outcome data | Measurement of outcome | Selection of reported result | Overall |
|---|---|---|---|---|---|---|
Fukase et al. (2024)52 | Low | Some concerns | Low | Low | Low | Some concerns |
Taguchi et al. (2023)53 | Low | Low | Low | Low | Low | Low |
Shinde et al. (2017)54 | Low | Some concerns | Some concerns | High | Some concerns | High |
Percentages |
|
|
|
|
|
|
Table 6: Study Characteristics and Key Findings for Chronic Musculoskeletal Pain
Reference (study type); Manufacturer’s sponsor | Target location | Topical treatment | Formulations (dose) | Comparator | Treatment duration | Efficacy | Safety |
|---|---|---|---|---|---|---|---|
Effect size (95% CI) OR Mean (SD) | |||||||
Fukase et al. (2024)52 (RCT) Yes | Low back pain | Diclofenac | DSSP (2 × 75 mg) per day | Oral tablet (75 mg) per day | 2 weeks | NR | Incidence of ulcers and/or erosions of GI: 26.7% vs. 86.2%; P < 0.0001 Serious AEs or withdrawals due to AEs: None |
Taguchi et al. (2023)53 (RCT) Yes | Low back pain | Diclofenac | Patch (75 mg) per day Patch (150 mg) per day | Placebo | 2 weeks | MD Pain
Similar results for responsea, disability, patient satisfaction, and global improvement. | All AEs: comparable among groups Serious AEs: None |
Shinde et al. (2017)54 (RCT) No | Chronic musculoskeletal pain (including OA) | Diclofenac | Patch (100 mg) once a day | Oral tablet SR 100 mg per day | 4 weeks | Pain: 3.32 (2.58) vs. 3.38 (2.67); NS Global improvement: 2.56 vs. 2.5; NS | AEs: 20% vs. 29.2% Epigastric pain/burning sensation: 4% vs. 8.3% |
AE = adverse event; CI = confidence interval; DSSP = diclofenac sodium systemic patch; GI = gastrointestinal; MD = mean difference; NR = not reported; NS = not statistically significant; OA = osteoarthritis; RCT = randomized controlled trial; SD = standard deviation; SR = slow release; vs. = versus.
aResponse: At least a 50% reduction in pain intensity
Table 7: Results of Quality and Bias Assessment of the Studies Included in the Systematic Reviews for Neuropathy
Study | Assessment tool | Description |
|---|---|---|
Ferraro et al. (2025)19 | RoB 2 |
|
Serednicki et al. (2022)30 | RoB 1 |
|
RoB 1 = original Cochrane risk-of-bias tool for randomized trials; RoB 2 = revised Cochrane risk-of-bias tool for randomized trials.
Table 8: Results of Quality and Bias Assessment of the Included Primary Study for Neuropathy
Study | Randomization process | Deviations from intended interventions | Missing outcome data | Measurement of outcome | Selection of reported result | Overall |
|---|---|---|---|---|---|---|
Ala et al. (2022)28 | Some concerns | Low | High | Low | Low | High risk of bias |
Table 9: Study Characteristics and Key Findings for Neuropathic Pain
Reference (study type); Manufacturer’s sponsor | Target location | Topical treatment | Formulations (dose) | Comparator | Treatment duration | Efficacy | Safety |
|---|---|---|---|---|---|---|---|
Effect size (95% CI) OR Mean (SD) | |||||||
Ferraro et al. (2025)19 (SR — 3 RCTs) No | Neuropathic pain | Ketamine | Solution (0.5%, 1%, 5%); 3 to 4 applications per day | Placebo | 2 days to 4 weeks | MD pain (immediate term) = 1.90 (−18.73 to 22.53) MD pain (short-term): 2.82 (−14.49 to 20.12) | RR AEs = 1.14 (0.47 to 2.73) RR withdrawal due to AEs = 1.14 (0.17 to 7.41) Serious AEs: NR |
Ala et al. (2022)28 (RCT) No | Diabetic neuropathy (arms, feet) | Baclofen | Cream (5%); 2 times per day | Placebo | 3 weeks | Pain:
After adjusting for gender and underlining diseases, P = 0.104 | AEs: None |
Serednicki et al. (2022)30 (SR — 3 RCTs) No | Diabetic neuropathy (feet) | Clonidine | Gel (0.1%) | Placebo | 8 weeks to 12 weeks | RR pain relief ≥ 50% = 1.21 (0.78 to 1.86) RR pain relief ≥ 30% = 1.35 (1.03 to 1.77) RR improvement (very much) = 1.82 (0.89 to 3.72) RR improvement (much or very much) = 1.06 (0.76 to 1.49) | RR AEs = 0.65 (0.14 to 3.05) RR withdrawal due to AEs = 0.34 (0.04 to 3.18) RR withdrawal due to lack of efficacy = 1.01 (0.06 to 15.92) RR serious AEs = 1.71 (0.70 to 4.22) |
AE = adverse event; CI = confidence interval; MD = mean difference; NR = not reported; RCT = randomized controlled trial; RR = relative risk; SD = standard deviation; SR = systematic review.
Table 10: Results of Quality and Bias Assessment of the Included Primary Studies for Anal Fissures
Study | Randomization process | Deviations from intended interventions | Missing outcome data | Measurement of outcome | Selection of reported result | Overall |
|---|---|---|---|---|---|---|
Bhatia (2025)36 | Some concerns | Some concerns | Low | High | Some concerns | High |
Sinha and Kumar (2024)39 | Some concerns | Some concerns | Low | High | Some concerns | High |
Agrawal et al. (2013)35 | Some concerns | Some concerns | Low | High | Some concerns | High |
Golfam et al. (2014)38 | Some concerns | Low | High | High | Low | High |
Golfam et al. (2010)37 | Some concerns | Some concerns | High | High | Some concerns | High |
Percentages | 100% - some concerns | 80% - some concerns; 20% - low risk of bias | 40% - high risk of bias; 60% - low risk of bias | 100% - high risk of bias | 80% - some concerns; 20% - low risk of bias | 100% - high risk of bias |
Table 11: Study Characteristics and Key Findings for Anal Fissures
Reference (study type); Manufacturer’s sponsor | Target location | Topical treatment | Formulations (dose) | Comparator | Treatment duration | Efficacy | Safety |
|---|---|---|---|---|---|---|---|
Effect size — Mean (SD) | |||||||
Bhatia (2025)36 (RCT) NR | Anus | Nifedipine | Cream (2%); 3 times per day | Oral tablet (10 mg); 3 times per day | 4 weeks | Patients with pain relief = 58.1% vs. 37.1%; P = 0.019 Patients with healing = 64.5% vs. 38.7%; P = 0004 Overall effectiveness = 21.0 vs. 38.7%; P = 0.668 | NR |
Sinha and Kumar (2024)39 (RCT) NR | Anus | Nifedipine | Ointment (0.2%); 3 times per day | Oral tablet (10 mg); 3 times per day | 8 weeks | Pain: 0.7 (1.58) vs. 1.11 (1.48); NS Healing: 92% vs. 73%; NS | NR |
Agrawal et al. (2013)35 (RCT) NR | Anus | Nifedipine | Ointment (0.2%); 2 times per day | Oral tablet (20 mg); 2 times per day Conservative treatment | 8 weeks | Pain:
Healing:
|
|
Golfam et al. (2014)38 (RCT) NR | Anus | Nifedipine | Cream (0.5%); 3 times per day | Oral tablet (10 mg); 3 times per day | 4 weeks | Pain:
Healing: 73% vs. 49%; P = 0.03 |
|
Golfam (2010)37 (RCT) NR | Anus | Nifedipine | Cream (0.5%); 2 times per day | Conservative treatment | 4 weeks | Pain relief: 75% vs. 20%; P < 0.005 Complete healing: 60% vs. 12%; P < 0.005 |
|
AE = adverse event; MD = mean difference; NR = not reported; NS = not statistically significant; RCT = randomized controlled trial; RR = relative risk; SD = standard deviation; VAS = visual analogue scale; vs. = versus.
Table 12: Results of Quality and Bias Assessment of the Studies Included in the Systematic Review for Vulvodynia
Study | Assessment tool | Description |
|---|---|---|
Ergisi et al. (2023)43 | NHLBI tool: before-after studies |
|
NHLBI = National Heart, Lung, and Blood Institute.
Table 13: Results of Quality and Bias Assessment of the Included Primary Study for Vulvodynia
Study | Randomization process | Deviations from intended interventions | Missing outcome data | Measurement of outcome | Selection of reported result | Overall |
|---|---|---|---|---|---|---|
Bornstein et al. (2010)40 | Low | Low | Low | Low | Some concerns | Some concerns |
Table 14: Study Characteristics and Key Findings for Vulvodynia
Reference (study type); Manufacturer’s sponsor | Target location | Topical treatment | Formulations (dose) | Comparator | Treatment duration | Efficacy | Safety |
|---|---|---|---|---|---|---|---|
Effect size | |||||||
Ergisi et al. (2023)43 (SR — 4 retrospective before-after studies) No | Vulva | Gabapentin | Gel (2%, 4%, 6%); 3 times per day | None | 8 weeks to 24 weeks |
|
|
Bornstein et al. (2010)40 (RCT) No | Vulva | Nifedipine | Cream (0.2%); 4 times per day Cream (0.4%); 4 times per day | Placebo | 6 weeks | In all 3 groups, mean pain intensity evaluated using various tests was reduced in the same degree at posttreatment compared to pre‑treatment. | Some patients in both nifedipine groups experienced mild irritation. |
NR = not reported; NRS = numeric rating scale; RCT = randomized controlled trial; SD = standard deviation; SR = systematic review.
Table 15: Results of Quality and Bias Assessment of the Included Primary Study for Pressure Ulcers
Study | Randomization process | Deviations from intended interventions | Missing outcome data | Measurement of outcome | Selection of reported result | Overall |
|---|---|---|---|---|---|---|
Zolfagharnezhad et al. (2021)41 | Low | Low | Low | Low | Low | Low |
Table 16: Study Characteristics and Key Findings for Pressure Ulcers
Reference (study type); Manufacturer’s sponsor | Target location | Topical treatment | Formulations (dose) | Comparator | Treatment duration | Efficacy | Safety |
|---|---|---|---|---|---|---|---|
Effect size (95% CI) | |||||||
Zolfagharnezhad et al. (2021)41 (RCT) NR | Buttock, upper back, around the hip bone, sacrum, others | Nifedipine | Ointment (3%); 2 times per day | Placebo | 2 weeks | MD ulcer intensity = −0.57 (−0.68 to −0.48); P < 0.001 MD ulcer size (cm2) = −1.42 (−2.05 to −0.81); P < 0.001 | Local AEs: None |
AE = adverse event; CI = confidence interval; MD = mean difference; NR = not reported; RCT = randomized controlled trial; vs. = versus.
Table 17: Results of Quality and Bias Assessment of the Studies Included in the Systematic Review for Acute Musculoskeletal Pain
Study | Assessment tool | Description |
|---|---|---|
Wiffen and Xia (2020)45 | RoB 1 |
|
RoB 1 = original Cochrane risk-of-bias tool for randomized trials.
Table 18: Results of Quality and Bias Assessment of the Included Primary Studies for Acute Musculoskeletal Pain
Study | Randomization process | Deviations from intended interventions | Missing outcome data | Measurement of outcome | Selection of reported result | Overall |
|---|---|---|---|---|---|---|
Ketoprofen | ||||||
Serinken et al. (2020)24 | Some concerns | Low | Low | Low | Low | Some concerns |
Serinken et al. (2016)23 | Some concerns | Low | Low | Low | Low | Some concerns |
Seidel et al. (2016)22 | Some concerns | Low | Low | Low | Low | Some concerns |
Percentages | 100% - some concerns | 100% - low | 100% - low | 100% - low | 100% - low | 100% - some concerns |
Diclofenac | ||||||
Pabst et al. (2023)55 | Low | Low | Low | Low | Low | Low |
Bukhari et al. (2022)56 | Some concern | Some concerns | Low | High | Some concerns | High |
Yin et al. (2022)57 | Low | Low | Low | Low | Low | Low |
Predel et al. (2020)58 | Some concerns | Low | Low | Low | Low | Some concerns |
Lai et al. (2017)59 | Low | Low | Low | Low | Low | Low |
Predel et al. (2016)60 | Some concerns | Low | Low | Low | Low | Some concerns |
Percentages |
|
|
|
|
|
|
Table 19: Study Characteristics and Key Findings for Acute Musculoskeletal Pain
Reference (study type); Manufacturer’s sponsor | Target location | Topical treatment | Formulations (dose) | Comparator | Treatment duration | Efficacy | Safety |
|---|---|---|---|---|---|---|---|
Effect size (95% CI) | |||||||
Serinken et al. (2020)24 (RCT — Children in ED) NR | Ankle sprain | Ketoprofen | Gel (2.5%), 2 g | Placebo | Follow-up: 15 and 30 minute after administration of the drug | MD pain
Difference in rescue drug = −10.9 (−16 to 7); P = 0.83 | AEs: None |
Serinken et al. (2016)23 RCT — Adults in ED NR | Ankle sprain | Ketoprofen | Gel (2.5%), 2 g | Placebo | Follow-up: 15 and 30 minute after administration of the drug | MD pain
Difference in rescue drug = −10.9 (−16 to 7); P = 0.02 | AEs: None |
Seidel et al. (2016)22 RCT Yes | Muscle soreness following exercise | Ketoprofen | Ketoprofen (100 mg) in Transferosome gel + oral placebo Ketoprofen (200 mg) in Transferosome gel + oral placebo | Oral ketoprofen (100 mg) in Sequessome vesicles + placebo gel Placebo gel + oral placebo | 1 week | Muscle pain scores:
Similar findings for recovery time to muscle soreness, and proportion of patients without pain at end of study | Treatment-related AEs, application site AEs and dermal AEs: higher with gel (200 mg) No serious AEs |
Wiffen and Xia (2020)45 (SR - 23 RCTs; 18 RCTs contained a placebo arm, and 9 provided dichotomous data) Yes | Sprains, strains, or contusion; usually sport-related injuries | Diclofenac | Patch (± heparin), gel (1%, 2.32%), spray gel (4%); 2 to 4 times per day | Placebo | At least 5 days, and up to 3 weeks, with most studies lasting 7 to 14 days | Clinical success (≥ 50% reduction in pain):
Similar findings were found for different formulations (i.e., Flector plaster, plaster with heparin, Voltaren Emulgel, spray gel) | RR local AEs (redness or erythema, and itch or pruritus) = 0.79 (0.58 to 1.07) RR systemic AEs = 0.91 (0.65 to 1.28) RR withdrawal due to AEs = 1.0 (0.46 to 2.15) |
Pabst et al. (2023)55 (RCT) Yes | Limb injuries or contusions | Diclofenac | Diclofenac sodium plaster (140 mg); once a day Diclofenac epolamine plaster (180 mg); 1 a day | Placebo | 1 week | MD pain vs. placebo:
| Irritation, erythema, itching, burning and withdrawal due to AEs: Similar in all groups Serious AEs: none |
Bukhari et al. (2022)56 (RCT) No | From sport injuries. Target: NR | Diclofenac | Diclofenac potassium gel (2%, 4%, 6%) Diclofenac sodium gel (4%) 3 to 4 times per week, with or without phonophoresis | Placebo | 4 weeks | Reported in graphs and P values. Overall, pain, stiffness, and physical function scores in patients treated with gel combined with or without phonophoresis were significantly decreased in a dose-dependent manner. Phonophoresis increased these benefits. Gels were more effective than placebo. | NR |
Yin et al. (2022)57 (RCT) Yes | Ankle sprain | Diclofenac | Diclofenac diethylamine gel (1.16%); 4 times per day | Diclofenac diethylamine gel (2.32%); 2 times per day | 1 week | MD pain = −0.76 (−4.23 to 2.70) MD tenderness = 1.46 (−1.83 to 4.74) MD joint function = 2.12 (−2.29 to 6.54) MD swelling = −0.38 (−0.66 to − 0.10) | Treatment-related AEs: NS between groups Serious AEs: None |
Predel et al. (2020)58 (RCT) Yes | Acute back or neck pain | Diclofenac | Diclofenac gel (2%) Diclofenac gel (2%) + capsaicin gel (0.075%) | Placebo gel Capsaicin gel (0.075%) | 5 days | Pain:
| AEs: Higher incidence in diclofenac + capsaicin or capsaicin alone (burning sensation, skin and subcutaneous disorders) |
Lai et al. (2017)59 (RCT) Yes | Ankle sprain | Diclofenac | Diclofenac 1% gel Diclofenac 1% gel + menthol 3% gel | Placebo gel Menthol 3% gel | 10 days | Pain, swelling, patient global assessment in response to treatment: NS difference among groups | Higher incidence of application site events with diclofenac 1% gel + menthol 3% gel group: dryness, pain, pruritus, erythema. |
Predel et al. (2016)60 (RCT) Yes | Limb (Soft tissue injuries of limbs from sport activities) | Diclofenac | Patch (140 mg); 2 times per day | Placebo | 1 week | MD pain at day 2 = −24.25 (−29.77 to −18.73); P < 0.001 Similar results were found for pain on movement and at rest, pain on pressure, time to efficacy onset, and global patient and investigator efficacy assessment. | Local AEs (dryness, erythema, pruritus): comparable between groups Serious AEs: None |
AE = adverse event; CI = confidence interval; ED = emergency department; MD = mean difference; min = minute; NNT = number needed to treat; NR = not reported; NS = not statistically significant; RCT = randomized controlled trial; RR = relative risk; SD = standard deviation; SR = systematic review; vs. = versus.
Table 20: Results of Quality and Bias Assessment of the Included Primary Studies for Cancer-Related Pain or Conditions
Study | Randomization process | Deviations from intended interventions | Missing outcome data | Measurement of outcome | Selection of reported result | Overall |
|---|---|---|---|---|---|---|
Giralt et al. (2020)31 | Low | Low | Low | Low | Low | Low |
Santhosh et al. (2024)61 | Low | Low | Low | Low | Low | Low |
Yamaguchi et al. (2021)62 | Low | Low | Low | Low | Low | Low |
Percentages | 100% - low risk of bias | 100% - low risk of bias | 100% - low risk of bias | 100% - low risk of bias | 100% - low risk of bias | 100% - low risk of bias |
Table 21: Study Characteristics and Key Findings for Cancer-Related Pain
Reference (study type); Manufacturer’s sponsor | Target location | Topical treatment | Formulations (dose) | Comparator | Treatment duration | Efficacy | Safety |
|---|---|---|---|---|---|---|---|
Effect size (95% CI) | |||||||
Giralt et al. (2020)31 (RCT) Yes | Mouth (oral mucositis derived from chemoradiation therapy for head and neck cancer) | Clonidine | Topical mucobuccal tablet 50 mcg, 100 mcg | Placebo | Starting 1 to 3 days before and continuing during cancer treatment | % of severe oral mucositis:
Same results for all other outcomes:
| Significantly lower incidence of nausea, dysphagia, vomiting, weight loss, and oral fungal infection was seen in the clonidine group compared to placebo group. |
Santhosh et al. (2024)61 (RCT) Yes | Capecitabine-associated HFS | Diclofenac | Gel (1%); 1 g per hand, 2 times per day | Placebo | 12 weeks or until development of HFS |
| AEs: No difference between groups Common AES in both groups: diarrhea, mucositis No cardiovascular AEs |
Yamaguchi et al. (2021)62 (RCT) Yes | Cancer of chest, abdomen, upper arm, back, lumbar region, and thigh | Diclofenac | Patch (from 150 mg/day to 225 mg/day); 1 time per day | Placebo | 2 to 4 weeks: open-label dose-titration phase 4 weeks: double-blind phase | The time to insufficient analgesic response was longer in diclofenac group than in placebo group (P = 0.0016) HR insufficient response = 0.459 (0.275 to 0.768) More patients in the diclofenac group achieved pain relief, satisfied with the treatment, and had “very good or good” sleep than those in the placebo group. | AEs: No difference between groups |
AE = adverse event; ARD = absolute risk difference; CI = confidence interval; HFS = hand-foot syndrome; HR = hazard ratio; NS = not statistically significant; QoL = quality of life; RCT = randomized controlled trial; SD = standard deviation
ISSN: 2563-6596
Canada’s Drug Agency (CDA-AMC) is a pan-Canadian health organization. Created and funded by Canada’s federal, provincial, and territorial governments, we’re responsible for driving better coordination, alignment, and public value within Canada’s drug and health technology landscape. We provide Canada’s health system leaders with independent evidence and advice so they can make informed drug, health technology, and health system decisions, and we collaborate with national and international partners to enhance our collective impact.
Disclaimer: CDA-AMC has taken care to ensure that the information in this document was accurate, complete, and up to date when it was published, but does not make any guarantee to that effect. Your use of this information is subject to this disclaimer and the Terms of Use at cda-amc.ca.
The information in this document is made available for informational and educational purposes only and should not be used as a substitute for professional medical advice, the application of clinical judgment in respect of the care of a particular patient, or other professional judgments in any decision-making process. You assume full responsibility for the use of the information and rely on it at your own risk.
CDA-AMC does not endorse any information, drugs, therapies, treatments, products, processes, or services. The views and opinions of third parties published in this document do not necessarily reflect those of CDA-AMC. The copyright and other intellectual property rights in this document are owned by the Canadian Agency for Drugs and Technologies in Health (operating as CDA-AMC) and its licensors.
Questions or requests for information about this report can be directed to Requests@cda-amc.ca.