Pain is the leading reason for visiting a doctor worldwide
According to published data, chronic pain accounts for 50% of all cases in Europe. Most likely, this figure will increase in the future, especially in older people, whose general condition is aggravated by various concomitant pathologies and has a complex etiology. Consequently, the need for safe and effective pain management increases in these patients. Specialists cannot completely relieve pain unless its cause is determined [1]. The International Association for the Study of Pain (IASP) defines it as “…an unpleasant feeling and emotional experience associated with actual or possible tissue damage or potential damage” [2]. Each patient perceives pain differently - depending on the irritant, previous experience and current psychological and physical state. The factors that cause pain cannot be ignored. They affect our behavior and mental activity, causing anxiety and/or depression [3,4]. Management of mild to moderate pain has traditionally relied on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the synthetic non-opioid analgesic paracetamol (acetaminophen). In cases of persistent syndrome and increased pain, it is possible to take weak opioids (such as codeine, dextropropoxyphene or tramadol) and even stronger opioids (such as morphine or fentanyl) together with NSAIDs or paracetamol. NSAIDs play a major role in the relief of pain in acute and chronic rheumatic diseases, as well as pain in the postoperative period (unlike paracetamol, these drugs can also relieve inflammation associated with these types of pain). The well-known gastrointestinal side effects of NSAIDs can be reduced by careful monitoring of dosages and duration of treatment, adequately prescribed treatment, and administered concomitantly with NSAIDs. On the other hand, to reduce side effects and complications from the gastrointestinal tract, selective cyclooxygenase-2 (COX-2) inhibitors have been developed. Unfortunately, large-scale studies have revealed that these substances have a potential even more serious side effect - cardiovascular complications. The European Medicines Agency (EMA) and the Food Supplement and Drug Administration (FDA) of the United States have developed standards regarding the need for caution and certain restrictions when prescribing COX-2 inhibitors, especially to patients with increased cardiovascular risk and for long-term use.
Lysine salt of ketoprofen
Ketoprofen is an NSAID of the family of propionic acid derivatives with analgesic, anti-inflammatory and antipyretic effects [5]. It is a racemic mixture, of which only the S isomer inhibits cyclooxygenase; the R-isomer has a much lower ability to do this [6,7]. Solification of ketoprofen with a lysine amino acid makes it possible to improve the pharmacological characteristics of the molecule [8,9]. In particular, the lysine salt of ketoprofen (LSK) has greater solubility than ketoprofen; this promotes accelerated and more complete absorption of the active substance. Consequently, a high peak concentration of the substance in the blood serum is achieved as quickly as possible - after 15 minutes. after oral administration of LSC (when taking ketoprofen this occurs after 60 minutes) (Fig. 1) [10–12]. Such a rapid increase in plasma LSC concentration further accelerates pharmacological activity. The pronounced analgesic effect of LSC appears within 30 minutes. after the first dose (statistically significant compared with placebo) [13]. In addition, the high solubility of LSC in aqueous media allows the administration of injectable drugs with a similar physiological pH level (without the need for preservatives) with a minimum of irritation reactions and tissue damage at the injection site. The main mechanism of the analgesic effect of LSC is the inhibition of cyclooxygenase (COX), and therefore a decrease in the production of prostaglandin E2 (PGE2). In addition to its effect on COX, ketoprofen inhibits the lipoxygenase pathway of the arachidonic acid cascade [14], leading to a decrease in the synthesis of leukotrienes. It is worth noting that the lysine salt of ketoprofen has both peripheral and central effects [15] due to the inhibition of PGE2 biosynthesis [16,17]. In this case, inhibition of nitric oxide synthase and COX occurs in the brain. Thus, the lysine salt of ketoprofen easily and quickly penetrates the central nervous system, passing the blood-brain barrier within 15 minutes. (due to the high level of lipophilicity) [18]. Recently, experts have demonstrated that the lysine salt of ketoprofen interacts with the 5-HT system. This suggests that this characteristic is a possible explanation for the high effectiveness of this drug compared to other NSAIDs [7,15,19]. These properties allow us to evaluate the lysine salt of ketoprofen as a means to reduce the symptoms of pain during inflammation of the musculoskeletal system that occurs in conditions of both acute and chronic disease [20]. As an NSAID, it is a powerful and highly effective agent for reducing pain in injuries, orthopedic and rheumatic pathologies due to its anti-inflammatory and analgesic properties [21].
Currently, the problem of painless tissue healing in the postoperative period still remains relevant. Despite the fact that a dentist’s arsenal includes various analgesic drugs that can provide pain relief even after fairly large and lengthy interventions in the oral cavity, the effectiveness and safety of most of them remains at an insufficiently high level.
It should be noted that in outpatient surgical practice, operations are often slightly or moderately traumatic, but affect richly innervated tissues. A feature of such interventions is that sometimes the surgical wound on the mucous membrane remains open and heals by the mechanism of secondary intention. For example, after taking a free gum graft from the palate in order to eliminate periodontal tissue recession, vestibuloplasty surgery, correction of lip frenulum. Healing of an open surgical wound is quite long and can take up to 7-10 days. In addition, due to the impossibility of completely isolating the wound surface from the food bolus, it is constantly irritated, which sometimes gives patients very strong pain while eating, as well as when talking. It should also be taken into account that after surgical interventions, inflammatory processes in the oral mucosa very often appear.
In this regard, drugs that have both anesthetic and anti-inflammatory effects are of great interest. These include drugs from the group of non-steroidal anti-inflammatory drugs (NSAIDs), which are most often prescribed by dentists after surgical interventions.
Ketoprofen, an NSAID, a derivative of propionic acid, whose mechanism of action is associated with inhibition of the enzyme cyclooxygenase, is widely used in dental surgery, resulting in a decrease in the synthesis of the main mediators of pain and inflammation - prostaglandins, cytokines and leukotrienes, which determines the pronounced anti-inflammatory and analgesic effect of the drug [1 , 2].
Of particular interest is the use of lysine salt of ketoprofen (LSK) (trade name “OKI”, manufacturer Dompe S.p.A., Italy). This is due to the fact that the combination of ketoprofen with the amino acid lysine made it possible, on the one hand, to significantly improve the pharmacokinetic properties and effectiveness of the active substance, and on the other, to improve its safety profile. This is expressed in increased solubility of the drug, increased bioavailability for tissues, faster absorption and the onset of action within 15 minutes with the achievement of a full therapeutic effect 30 minutes after administration [3]. OKI has a neutral pH and almost does not irritate the gastrointestinal tract, and therefore the risk of developing the most common undesirable effects of NSAIDs - gastropathy of varying severity - is reduced. LSC is the only systemic form of ketoprofen approved for use in pediatric practice from the age of 6 years.
The effectiveness and safety of LSC have been confirmed in numerous foreign clinical studies. In a randomized study on the use of LSC, the high analgesic and anti-inflammatory activity of the drug was proven in dental patients with inflammatory diseases of the oral cavity and post-traumatic pain [3]. The analgesic effectiveness of OCI is higher and faster than that of paracetamol, which is a good alternative to using the drug to reduce pain, especially in childhood [6]. Along with this, good tolerability of LSC was demonstrated at the placebo level and 1.6 times better in comparison with conventional ketoprofen [3, 4].
Considering the characteristics of the surgical wound, local use of NSAIDs may be no less relevant and effective. Today, for ease of use, the drug OKI has various forms of release - both systemic in the form of sachets containing granules for the preparation of a solution for oral administration, rectal suppositories for children 60 mg and adults 160 mg, and local action. The advantage of using the dosage form “solution for local use” is the absence of a pronounced systemic pharmacological effect. In dental practice, the drug provides a targeted effect on the source of pain and inflammation and can be used for gingivitis, glossitis, periodontopathies, chronic periodontal disease, in the presence of ulcers on the oral mucosa due to stomatitis, trauma, after dental interventions and tooth extraction. Foreign studies have shown that LSC in the form of a solution for local use has a pronounced analgesic and anti-inflammatory effect in the presence of local symptoms of inflammation and pain in the oral cavity [5, 7]. However, in the domestic literature there are no works on the use of LSC in dental practice, which was the basis for conducting this study.
The purpose of the study was to study and evaluate the clinical effectiveness and safety of the use of LSC (OCI) in the form of a sachet and solution for topical use in patients after various dental surgical interventions. In addition, it was of interest to compare the analgesic effect of the systemic and local forms of the drug depending on the type and extent of surgical intervention.
Material and methods
The examination was carried out on the basis of the Department of Surgical Dentistry and Maxillofacial Surgery in the surgical department of the dental clinic of the Nizhny Novgorod State Medical Academy. 30 patients of both sexes aged from 21 to 52 years were observed.
The selection criterion was: voluntary informed consent of patients to treatment and participation in the study. To achieve this goal, dental treatment and examination of patients were carried out after the following surgical interventions: vestibuloplasty with an apically displaced flap with collection of a free gum graft from the palate - 11 (37%) people (5 men and 6 women); removal of impacted and dystopic teeth - 10 (33%) people (6 men and 4 women); tooth-preserving operations - 9 (30%) people (5 men and 4 women).
The observed patients were prescribed the drug LSC (manufactured by Dompe S.p.A., Italy), produced under the trade name OKI.
On the 1st day after surgery, patients took OKI at a dose of 80 mg (contents of 1 double sachet) in the form of granules for the preparation of a solution for oral administration 2-3 times a day after meals. From the second day, only LSA solution was used in the form of rinses 2-3 times a day.
Method of local application - 2-3 baths per day, 10 ml of OKI solution (5 injections) per dose. A solution of 5 injections (1 injection - 2 ml of OKI solution) should be diluted in a glass supplied with the package, half filled with drinking water. Accidental ingestion of rinse solution does not lead to serious consequences, because... a single dose for rinsing contains 160 mg of LSC, which corresponds to the dose intended for oral administration.
To objectively assess the severity of pain, the pain intensity scale was used (Fig. 1).
Figure 1. Pain intensity scale.
The patient was asked to rate the level of pain from 0 to 10 before and after using the OCI drug. Evaluation criteria: 0 - no pain, 1-3 - mild pain, 4-6 - moderate pain, 7-8 - severe pain, 9-10 - very severe unbearable pain. Possible undesirable effects were also taken into account.
Results and discussion
Clinical observations showed that the analgesic effect was achieved in all patients taking LSC.
At the same time, patients after vestibuloplasty with an apically displaced flap with collection of a free gum graft from the palate (Fig. 2)
Figure 2. Assessment of the intensity of pain during vestibuloplasty using an apically displaced flap with collection of a free gum graft from the palate. noted a significant decrease in pain already on the day of surgery after the first use of the drug from 5.18±0.31 to 3.02±0.10 (p<0.001), which corresponds to the scale.
After tooth-preserving operations (Fig. 3)
Figure 3. Assessment of pain intensity during tooth-preserving operations. — the decrease in pain on the day of surgery averaged from 5.21±0.44 to 2.06±0.36 (p<0.001), which corresponds to the scale.
After surgery to remove an impacted and dystopic tooth (Fig. 4)
Figure 4. Assessment of the intensity of pain during surgery to remove impacted and dystopic teeth. a decrease in pain was noted from 6.25±1.02 to 3.75±0.12 (p<0.05), which corresponds to the scale, but was more significant by the 2nd day.
It was noted that after tooth-preserving operations and removal of impacted and dystopic teeth, where the wound was closed after surgery, a more pronounced and rapid effect was observed after using the OCI drug orally in the form of a sachet, while local application of the OCI solution was less effective. At the same time, in the presence of an open wound after vestibuloplasty surgery and collection of a free gum graft from the palate, the effectiveness of both forms of the drug was comparable, and patients also noted a faster onset of anesthesia of the surgical wound when using the OCI solution, in comparison with the use of the OCI drug orally in the form sachet.
The analgesic effect was observed after 20-30 minutes and persisted in the postoperative period for an average of 8 hours. There were no adverse reactions to the use of OKI.
Conclusion
Thus, the lysine salt of ketoprofen (OKI) has high analgesic effectiveness, and in the form of a solution for topical use, its safety increases. In the absence of contraindications, OKI can be recommended as the drug of choice for relieving pain and inflammatory processes in the oral cavity after dental procedures.
The use of ketoprofen in chronic rheumatic diseases
Osteoarthritis (OA) is the most common joint disease. In the study, 113 patients with symptoms of coxarthrosis underwent a 4-week course of comparative treatment with oral administration of ketoprofen or indomethacin. The study showed a significant effect in reducing pain and improving joint function, thereby improving the quality of life of patients. At the same time, taking ketoprofen turned out to be safer: fewer patients suffered from side effects or dropped out of the study [22]. Good effectiveness of oral administration of LSC has been shown in patients with OA: improvement was observed in 67.6% of patients [23]. Moreover, the analgesic effectiveness of LSC in acute conditions was higher than that of acetylsalicylic acid: the level of β-endorphin circulation in plasma was higher, and the level of substance P was lower. These data suggest that the rapid and continuous analgesic effect of the drug in patients with OA may be associated specifically with the level of β-endorphin and substance P in the circulatory system [24]. Rheumatoid arthritis (RA) is a chronic inflammatory disease of peripheral joints, often leading to tissue degradation and destruction of bone and cartilage [25]. Therapy is aimed at eliminating the inflammatory consequences of autoimmune activation using antirheumatic drugs that modulate the disease (“basic”). Systemic glucocorticoids are effective for short-term relief of pain and synovitis. Analgesics are used to reduce pain at all stages of the disease, often in combination with other treatments to control the inflammatory process. NSAIDs reduce pain and stiffness quickly without affecting the course of the disease. Numerous data indicate that both classical NSAIDs and those selective for COX-2 are better at relieving active signs and symptoms of RA than simple analgesics [26]. An open-label, 1-week study of 26 patients with RA and persistent synovitis of the knee demonstrated that treatment with LSC and naproxen (NA) significantly reduced pain and improved other clinical parameters [27]. Moreover, the level of synovial prostaglandin 2 (PGE2) decreased significantly, especially as a result of taking LSC, by 62.8% (for naproxen by 51.7%, respectively). The overall effectiveness and tolerability of both courses of treatment were almost identical (slightly higher for LSC). The authors concluded that the use of LSC should be recommended for the symptomatic treatment of RA, since this study confirms the pronounced analgesic and anti-inflammatory effect, as well as the active inhibitory effect of LSC on the level of PG in the joint fluid (even compared with naproxen). In another study involving 34 patients with rheumatic diseases (20 of them had RA), experts noticed that oral administration of LSC significantly reduced pain. There was a significant reduction in spontaneous pain (p<0.001), pressure tenderness, functional limitations and duration of morning stiffness within 10 days of treatment in all study patients [23]. Moreover, in 10 patients with persistent synovitis of the knee, LSC also successfully penetrated into the synovial fluid, significantly reducing the level of PGE2 in it (inhibition was about 73%). For elderly patients, these data are of particular importance. They often suffer from rheumatic diseases such as OA and RA, which are associated with various associated conditions, and usually require long-term use of NSAIDs. Therefore, the issue of long-term use is important regarding the safety of treatment. It should be said that ketoprofen has been evaluated in extensive studies involving a group of elderly patients. In particular, a prospective study conducted to determine the safety profile of ketoprofen over 12 months. involving 823 patients over 65 years of age (with OA and RA; taking ketoprofen orally), showed the following. At the end of the study, 521 (63.3%) patients remained on the same therapy. Oral ketoprofen is safe for elderly patients with arthritis over a long period of time. Pain reduction and safety rates were similar to those seen in younger patients [28]. The safety of ketoprofen for use in the elderly was assessed in a large open-label study involving approximately 20,000 elderly patients (over 60 years of age) suffering from various rheumatic diseases. Oral ketoprofen for 4 weeks provided overall effectiveness, rated by physicians as “excellent”/“good” in 74% of cases, with a “very good” risk-benefit ratio in older patients compared with the rest of the population [29]. Gout is an acute inflammatory joint disease that affects 1–2% of adults in industrialized countries. It occurs when uric acid crystals accumulate in joints and other tissues [30–32]. With gout, recurrent attacks of acute arthritis often occur. Sometimes this leads to chronic arthropathy, salt deposits and kidney disease. Gout is also associated with a number of comorbid conditions, such as cardiovascular disease, chronic kidney disease and metabolic syndrome [32]. Standard treatments for acute gout attacks include glucocorticoids, NSAIDs, and colchicine [32–34]. To study the effect of ketoprofen in gouty arthritis, several studies have been conducted, showing that intramuscular or oral administration of ketoprofen for 1 week. effectively, quickly and significantly reduces pain [35,36]. In a 7-day, multicenter, double-blind study conducted to compare the effects of oral ketoprofen and indomethacin in 59 patients with acute gouty arthritis, more than 90% of patients reported a decrease in pain within 1 day of taking the drug. At the end of the study period, the majority of patients in both groups showed significant improvement (assessed by both the investigators and the patients themselves). In addition, the researchers concluded that ketoprofen can relieve pain in acute gouty arthritis within 24 hours with the same effectiveness, but with fewer side effects, than indomethacin, which is routinely prescribed for this condition [37].
Taking lysine salt of ketoprofen for acute rheumatic and traumatic diseases
Acute rheumatic and traumatic diseases, soft tissue injuries are often accompanied by pain, swelling and inflammation. These include: sprains, tendonitis, bursitis (eg, lateral epicondylitis (tennis elbow), regional musculofacial pain syndrome, low back pain, and neurovascular impingement (eg, carpal tunnel syndrome and superior outlet syndrome). A double-blind clinical trial of oral LSA (80 mg/3 times daily) was conducted versus placebo in 120 patients with soft tissue disorders (tendonitis, bursitis and periarthritis). associated with pain, functional impairment and painful sensitivity to any touch, as well as a rapid and pronounced reduction in pain itself. The analgesic effect of LSC became significant within 30 minutes after administration (Fig. 2). Moreover, due to adverse reactions to the drug not a single patient dropped out. It was noted that the drug was truly safe - just like placebo. In conclusion, it is worth saying that for patients with soft tissue diseases, oral administration of LSC (as the study showed) is effective and safe [38]. Another comparative multicenter study aimed to determine the effectiveness and tolerability of ketoprofen and diclofenac sodium in acute rheumatic and traumatic conditions. In 180 patients who took ketoprofen or diclofenac for 15 days (first in the form of intramuscular injections, then orally), a decrease in pain symptoms was noted. Ketoprofen is recognized as more effective as an analgesic used in most pathological conditions. The study also showed that ketoprofen was better tolerated than diclofenac. It is rated “excellent/good” based on the results obtained in the largest percentage of patients [39]. To compare the analgesic effect of 1-week administration of ketoprofen (50 mg/3 times daily orally) and ibuprofen (600 mg/2 times daily orally), a multicenter, double-blind study was conducted involving 165 patients with sports injuries. In these patients, the resulting injuries have caused a range of painful lesions such as tendinitis or tenosynovitis, epicondylitis, traumatic bursitis, sprain, or contusion. The results obtained showed that after the first (oral) dose, ketoprofen reduces pain significantly faster (by 1.1 hours) compared to ibuprofen. It also turned out that the maximum pain reduction score for ketoprofen was much higher. Within 6 hours, 76% of patients taking ketoprofen experienced a 50% reduction in pain; for those taking ibuprofen, the rate was 58% (p<0.05). The maximum degree of pain reduction was achieved faster with ketoprofen than with ibuprofen (Fig. 3) [40].
Lower back pain
Low back pain is one of the most common conditions encountered in clinical practice. The main method of treatment is medication. In terms of duration, acute low back pain is usually defined as a symptom that persists for at least 6 weeks, subacute pain - from 6 to 12 weeks, chronic low back pain - from 12 weeks. and longer. For most patients, regardless of how long symptoms last, paracetamol (acetaminophen) and NSAIDs are the first choice pain reliever. The results of oral and intramuscular ketoprofen have been studied in a number of different clinical studies involving patients suffering from lumbago. A comparative 1-week study of the effectiveness and tolerability of intramuscular ketoprofen and indomethacin involved 115 patients with acute low back pain. The study results showed that ketoprofen significantly reduced overall pain and provided more durable pain relief than indomethacin. In addition, it should be noted that already 1 hour after administration, more patients in the ketoprofen group experienced a significant reduction in pain than in the group taking indomethacin (61 and 46.9%, respectively) [41]. Another study of 155 patients with chronic low back pain found that oral ketoprofen (150 mg twice daily) produced higher rates of improvement than diclofenac (75 mg twice daily) after 1 day. weeks after reception. This means that thanks to ketoprofen, pain relief occurred earlier than when taking diclofenac (in 71.4 and 62.36% of patients, respectively).
