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Effectiveness and Safety of Oral Dexketoprofen for Mild to Moderate Pain among Filipino Adults: A Post-marketing Surveillance Study

Background: Studies abroad demonstrate the effectiveness and safety of dexketoprofen in various therapeutic indications. However, there has been no related study on our local population. Objectives: To evaluate the effectiveness and safety of oral dexketoprofen among Filipino adults in the treatment of mild to moderate acute pain due to musculoskeletal causes (such as osteoarthritis and low back pain), postoperative pain, headache, or dysmenorrhea in primary health care setting in the Philippines. Methods: This was a prospective observational study. Drug prescription by attending physicians was based on the drug’s Summary of Product Characteristics, which included its indications, contraindications, and precautions. Dosage prescriptions varied, depending on the nature and severity of pain on initial consultation, and physicians’ clinical judgment. Effectiveness was evaluated using Wong-Baker faces pain rating scale, clinical global impressions scale, and efficacy index; while safety was evaluated according to incidence and severity of adverse events. Results: Osteoarthritis and low back pain were the most common conditions seen by the physicians during the study period. Majority received the recommended dosage and duration of the medicine, which was 51-75 milligrams of dexketoprofen a day (56.2%) for at least 1 week (57.5%). On follow-up, there was statistically significant improvement (p<0.0001) in pain scores among patients, regardless of medical condition and dexketoprofen dosage and duration. There was low (2.8%) incidence of adverse events in the study population. Majority of side effects did not significantly interfere with daily functioning of patients. Conclusion: This study demonstrated the effectiveness and safety of oral dexketoprofen in various therapeutic indications. Majority experienced moderate or marked therapeutic effect with no to minimal side effect. No serious adverse event from intake of non-steroidal anti-inflammatory drug, particularly related to gastrointestinal and nervous system disorders was noted.


Introduction
Pain is the most common reason for consultation in primary care centers [1]. When not adequately addressed, pain can lead to loss of productivity and decrease in quality of life. Hence, it is necessary to treat pain aggressively with the least invasive treatment modality that is both effective and safe. For mild to moderate pain, non-steroidal antiinflammatory drugs (NSAID) remain as first-line in the World Health Organization analgesic ladder [2]. NSAIDs represent a large heterogeneous group of compounds used for treatment of inflammatory and painful conditions that can either be musculoskeletal or non-musculoskeletal in etiology. Their antiphlogistic, analgesic, and antipyretic actions are principally based on their ability to inhibit cyclooxygenase, which is the key enzyme in the production of prostaglandins from arachidonic acid [3].
Dexketoprofen is a recently developed NSAID with fast and powerful antiphlogistic action, accompanied by lesser gastric side effects than Ketoprofen [4]. It has slow-release formulation that can produce good penetration into joint space, confirmed by persistent therapeutic concentrations in serum and synovial fluid. Thus it can be administered as low as once a day to a maximum of three times a day, leading to improved compliance especially among patients with polypharmacy for comorbid diseases.
Musculoskeletal conditions, which are frequently characterized by pain and inflammation, are among the leading indications of NSAIDs. The musculoskeletal diseases commonly studied when evaluating the efficacy and safety of dexketoprofen were low back pain, osteoarthritis of hands and knees, ankle sprain, and lower limb trauma [5][6][7][8][9]. Postoperative pain serves as another important model of acute pain in the evaluation of analgesic efficacy and speed of action. In this model of pain, NSAIDs and opioids act synergistically to produce balanced, multimodal analgesia [10]. Other important models of pain include headache and dysmenorrhea, wherein prostaglandins play a pathogenic role; thus NSAIDs are clearly indicated [11].
When conducting post-marketing surveillance, both effectiveness and safety should receive equal emphasis. Several studies abroad show that there is no significant difference between dexketoprofen and other control analgesics in terms of effectiveness, and incidence and profile of adverse events in various therapeutic indications [12][13][14][15][16]. Therefore, the present study aimed to achieve the following objectives: • To evaluate the effectiveness of oral dexketoprofen in the treatment of mild to moderate acute pain due to musculoskeletal causes (such as osteoarthritis and low back pain), post-operative pain, headache, or dysmenorrhea in local primary health care setting, as measured by Wong-Baker faces pain rating scale, clinical global impressions scale, and efficacy index; and • To evaluate safety outcomes according to incidence and severity of adverse events among Filipino patients.

Methodology
This prospective observational study was conducted over a period of 23 months involving a cohort of patients seen in private clinics in different regions of the country and managed with oral dexketoprofen for mild to moderate acute pain due to any of the following causes: osteoarthritis, low back pain, post-operative pain, headache, or dysmenorrhea. The study was approved by the national Food and Drug Administration of the Department of Health. Good clinical practice guidelines were observed throughout the study.

Study procedure
Drug prescription by attending physicians was based on their clinical judgment and knowledge of the drug's Summary of Product Characteristics, which included its indications, contraindications, and precautions [17]. The physicians explained the dosage, potential benefits, and adverse effects of the drug to their patients. Dosage prescriptions varied, depending on the nature and severity of pain on initial consultation. Recommended dosage was generally one 12.5 milligram-tablet every 4 to 6 hours, or one 25 milligram-tablet every 8 hours taken 30 minutes before meal, or as long as total daily dose did not exceed 75 milligrams for healthy patients, or 50 milligrams for those with known mild hepatic or renal dysfunction.
The case report form had 3 main parts: 1) Patient's Clinico-Demographic Profile (including age, sex, weight, occupation, reason for consultation, dosage of oral dexketoprofen prescribed, duration of drug intake, co-morbid diseases, and polypharmacy); 2) Effectiveness Outcomes (including pain score, global improvement score, and efficacy index); and Safety Outcomes (including description and date of adverse events, causal relationship with dexketoprofen intake, severity, and measures taken).

Effectiveness assessment
Effectiveness was assessed based on the following outcomes Pain score: Physicians obtained subjective pain reports of patients at baseline and follow-up (i.e. after completing 7 days of drug intake, unless a patient presented with adverse event/s necessitating earlier follow-up and/or premature discontinuance of the drug). Based on Wong-Baker faces pain rating scale, pain scores were interpreted according to the following levels of severity: (0) "no pain;" (1) "mild, annoying pain;" (2) "nagging, uncomfortable, troublesome pain;" (3) "distressing, miserable pain;" (4) "intense, dreadful, horrible pain;" and Efficacy index: At baseline and follow-up, presence or absence of certain physical examination findings (i.e. swelling, deformity, tenderness, warmth, crepitus, joint effusion, and muscle atrophy) were documented among patients with musculoskeletal complaints (i.e. muscle and/or joint pains). Lastly as part of CGI-Efficacy Index, which plotted the therapeutic effect against adverse effects in a 4 × 4 table (Table 1), physicians reported their patients overall clinical outcomes according to their re-evaluation [19].  Table 1: Clinical Global Impression scale-efficacy index [19].

Safety assessment
Safety was assessed based on patient reports of adverse events according to frequency, severity, and causality. Each adverse event was classified as non-serious or serious based on the drug's Summary of Product Characteristics; the latter is defined as an event leading to lifethreatening medical condition, persistent incapacity, prolonged hospitalization, or death [17]. For any serious adverse event deemed causally related to dexketoprofen intake, physicians were instructed to immediately notify A. Menarini Philippines, Inc. for further investigation, intervention, and documentation. Causal relationship between study medication and adverse event was classified as "not related, " "unlikely, " "possibly, " "probably"or"definitely related" according to the modified algorithm by Karch and Lasagna [20].

Treatment of data
Descriptive statistics (i.e. frequency with percentage, mean with standard deviation, median, and range) was performed on demographic and clinical outcomes data, wherever applicable. Data analysis on safety assessment was performed based on the Safety Population, which included all patients who received at least one dose of the study medication during the observation period. All data related to safety assessment (i.e. serious or non-serious adverse events, causal relationship with intake of study medication, premature discontinuance of the drug, and concomitant medication, when needed for adverse event) of the safety population was reported in accordance to the standard operating procedure of the manufacturing company. Analytical statistics using chi-square test was performed on data related to effectiveness outcomes in the intention-to-treat population. All data were reported at 95% confidence interval.

Results
A total of 870 case report forms were submitted and analyzed. Table  2 shows the baseline characteristics of the patients.
Patients had a median (interquartile range) age of 42 (30-54) years, and weight of 62 (55-70) kilograms (Table 2). Majorities were females (54.3%), and were employed for skilled work (29.3%). The conditions that were seen by the physicians during the study were (in order of decreasing frequency): Peripheral muscle and/or joint pains (i.e. osteoarthritis) (53.4%); axial pain (i.e. low back pain) (18.7%); postoperative pain (7.5%); headache (6.6%); and dysmenorrhea (5.3%). More than half of the population received a daily dose of 51-75 milligrams of dexketoprofen (56.2%). Treatment compliance was high, such that majority followed their physician's advice to take the medication for at least 1 week (57.5%). Those who took it for less than 7 days discontinued either due to early pain relief or onset of adverse events; while those who took it for 2 weeks either due to persistent pain or fear of pain recurrence. About 1 out of 5 patients had at least 1 comorbid condition (23.7%), and took their other prescription drugs (37.7%) that were not for pain.

Effectiveness Outcomes
"Distressing, miserable" was the overall top pain description (36.3%) of patients at baseline. Majority of patients regardless of disease had baseline pain that ranged from "nagging, uncomfortable, and troublesome"to"intense, dreadful, and horrible. " Some patients, especially those with peripheral muscle and/or joint pains (i.e. osteoarthritis), described their pain as "worst, unbearable, excruciating. " On follow-up, majority reported to have had either "no pain" or "mild, annoying" pain, and there was neither report of "intense, dreadful, horrible" nor "worst, unbearable, excruciating" pain. The difference in pain reports between baseline and follow-up periods was statistically significant (p<0.0001, Mann-Whitney U test) in all pain conditions. Two hundred fifty physicians were able to indicate the scores of their patients at baseline and follow-up using the Clinical Global Impressions-Severity (CGI-S) and Improvement (CGI-I) scales, respectively. At baseline, majority of patients were either "moderately ill" (36.4%) or "mildly ill" (28.4%) ( Table 3). On follow-up, 54% of patients had "very much improved, " while the rest either had "much improved" (27.6%), "minimally improved" (5.2%), or "no change" (1.2%) ( Table 3). Overall, 86.8% of the population had improved, regardless of degree of improvement. There was no report of worsening from baseline. Among patients with peripheral myalgia and/or arthralgia (i.e. osteoarthritis), which was the most common pain condition (n=465) in the study population, certain clinical parameters were evaluated at baseline and follow-up (  Furthermore, the CGI-Efficacy Index (Table 5) showed that majority (56.4%) had marked therapeutic effect with no side effect on follow-up. Approximately 11% either had marked improvement with side effect that did not significantly interfere with functioning or moderate improvement without side effect (Table 5). On the other hand, 1.3% (3 out of 230 patients) did not improve.

Safety Outcomes
As shown in Table 6, 2.8% of the population reported at least one adverse event (AE), which most commonly occurred among patients with low back pain (9 cases), peripheral muscle and/or joint pains like osteoarthritis (5 cases); and headache (4 cases). Patients treated for headache reported the highest proportion of adverse events (4 out of 57 cases; or 7.0%), followed by those with dysmenorrhea (3 out of 46 cases; or 6.5%), and low back pain (9 out of 163 cases; or 5.5%).
Adverse events were most commonly related to the gastrointestinal tract (i.e. bloatedness, constipation, epigastric pain, or hypogastric pain) (7 out of 870 cases; 0.8%) and nervous system (i.e. dizziness, nausea, or insomnia) (6 out of 870 cases; 0.7%) ( Table 6). Majority of AEs were classified as non-serious (Table 7). One case of serious AE that necessitated hospital admission was related to hyperglycemia in a patient with low back pain. The other 4 serious AEs were unclassified or lacked adequate information in the physicians case report forms.  Approximately 71% of the AEs were either "not" (7 out of 24) or "possibly" (10 out of 24) related to dexketoprofen intake, and 16.7% were classified as "definitely related" (Table 7). Among the 4 patients who developed AEs "definitely related" to drug intake, 1 had fever, 1 had periorbital edema, 1 had disturbance in the gastrointestinal tract (i.e. bloatedness), and the other 1 was unclassified or undetailed. Definitely Related n=4

Discussion
Musculoskeletal conditions, particularly osteoarthritis and low back pain, were the most common conditions seen by physicians throughout the study period. Majority received the recommended dosage and duration of the medicine, which was 51-75 milligrams of dexketoprofen a day (56.2%) for at least 1 week (57.5%). On follow-up, there was statistically significant improvement (p<0.0001) in pain scores among patients, regardless of medical condition and dexketoprofen dosage and duration. There was low (2.8%) incidence of adverse events in the study population. Majority of these adverse events did not significantly interfere with daily functioning of patients (Table 5).
Osteoarthritis, which remains to be one of the most common musculoskeletal conditions managed in ambulatory clinics, causes somatic type of pain. It is considered an important standard for measuring analgesic efficacy, especially in acute exacerbations [6][7]. Low-back pain and its consequent restriction on mobility is likewise a common condition, wherein inflammation of soft tissues and paralumbar spasm can be addressed by NSAIDs [21]. A medicine's fast onset of action is crucial in the prevention of antalgic postures, which might delay recovery or cause more pain.
In general, the frequency and severity of adverse events (AEs) reported in this local study were comparable in previous studies abroad [2,8,13]. Majority of AEs were classified as non-serious. The incidence and profile of AEs remain within the expected range for a drug of this pharmacological class, being mild gastrointestinal adverse reactions (i.e. bloatedness, constipation, epigastric pain, or hypogastric pain) as most frequent, followed by neurologic disorders system (i.e. dizziness, nausea, or insomnia), which were similar to related studies [2,8]. In our study, it is worth noting that no serious adverse event, particularly gastrointestinal bleeding, myocardial infarction, or death, was reported.
Limitations of the study include data collection that had missing data or unclear responses. For instance, there were 4 serious AEs that could have been classified if there were more details provided by the physician-participants. In addition, there was limitation in the returnrate of responses in terms of the CGI (Clinical Global Impressions) scales, wherein only 250 physicians were able to report the scores of their patients. Since the case report forms were designed to protect the anonymity of patients and physicians alike, there was no provision for information on contact details to clarify vague or missing responses. Recall bias might have also affected the accuracy of responses of both patients and physicians. We also do not discount the possibility of over-or underreporting of both therapeutic effect and adverse events from either party. Moreover since the study was conducted in private clinics, physicians might have committed selection bias of patients who seemed to be more cooperative and compliant than the rest. Hawthorne effect might have influenced the outcomes to lean more towards benefit than risk. Therefore, it is recommended that aforementioned limitations be addressed in future related studies to improve the methods and prevent bias. Future studies can also compare dexketoprofen with other commonly prescribed non-steroidal anti-inflammatory medications with respect to effectiveness and safety.

Conclusion
In conclusion, majority of the study population experienced moderate or marked therapeutic effect with no to minimal side effect. The most common conditions that were relieved with oral dexketoprofen included musculoskeletal complaints, such as osteoarthritis and low back pain. This post-marketing surveillance provides a view of the effectiveness and safety of the medication.