Dolmen’s place in the palette of nonsteroidal anti-inflammatory drugs (NSAIDs)

Modern pain management recommendations place a lot of emphasis on educating the patient, their family, and medical staff on how to prevent pain. However, if a patient needs pharmacological pain management, non-steroidal anti-inflammatory drugs (NSAIDs) are usually the first choice. These drugs effectively reduce inflammation, lower fever, and most importantly, they are effective in relieving pain of various origins. NSAIDs are among the most commonly used drugs in clinical practice [1, 2, 3]. In the United States, about 5% (approximately 17 million) of patients visit doctors to get prescriptions for them [1, 2].

Briefly about NSAIDs
The first NSAID, sodium salicylate, was discovered in 1763. Salicylates often caused gastrointestinal complications. The most widely used and researched was acetylsalicylic acid, also known as aspirin, discovered by Friedrich Bayer in 1898. Continuing research, the first non-salicylate group NSAID was discovered in 1950 – phenylbutazone (an indole acetic acid derivative) aimed at reducing inflammation. However, due to the observed toxic effects on bone marrow, the drug was discontinued. In 1960, another indole acetic acid derivative – indomethacin entered the market, which successfully marked the era of safer NSAIDs. Currently, there is a wide selection of NSAIDs on the market: there are more than 20 types of NSAIDs, and their number is constantly increasing, making it difficult for clinical practice doctors to choose. When developing new NSAIDs, the focus is not only on pain and inflammation relief but also on safety of use and less frequent adverse reactions.
NSAIDs reduce pain and inflammation by acting on the cyclooxygenase (COX) enzyme isoforms [4]. The effect of NSAIDs is explained by inhibiting prostaglandin synthesis in peripheral tissues and in the central and peripheral nervous system. Prostaglandins are formed from arachidonic acid by acting on endoperoxidase, which consists of COX and hydroperoxidase. There are two well-known COX isoforms: the first, or constitutive (COX-1), and the second, or inducible (COX-2); in recent years, a third cyclooxygenase (COX-3) has been studied [4]. COX-1 regulates many physiological functions of prostaglandins: protection of the stomach mucosa, kidney tubule function, vasodilation in the kidneys, bronchodilation, promotion of vasodilation in the kidneys, production of vasodilating prostacyclin (it inhibits platelet adhesion), promotes thromboxane production and secretion from platelets, their aggregation and blood vessel spasm [4]. The COX-2 isoform is involved in prostaglandin synthesis at the site of inflammation, influencing kidney hemodynamics. Tissue damage stimulates COX-2 production and the production of pro-inflammatory prostaglandins, which cause pain and inflammation, while in the spinal cord, COX-2 can affect the sensitization of the central nervous system. Moreover, COX-2 naturally exists in kidney, heart, and vascular system tissues, as well as in the brain [4].
Based on how the inhibitory enzyme works, all NSAIDs are classified into selective and non-selective COX-1 and COX-2 inhibitors. Single doses of non-selective NSAIDs are usually quite effective in treating postoperative pain [5], renal colic [6], primary dysmenorrhea [7], and postoperative pain [8–10]. However, for severe postoperative pain relief, NSAIDs are often combined with opioid analgesics – this reduces the consumption of the latter, along with the frequency of their side effects (nausea, vomiting, suppression) [11, 12].

Dexketoprofen (Dolmen)
Dexketoprofen trometamol is the tromethamine salt of S-(+)-2-(3-benzoylphenyl)propionic acid. Its analgesic effect, determined by its structure (S(+) enantiomer), is equivalent to the effectiveness of a double dose of ketoprofen, but the undesirable effect of dexketoprofen on the gastrointestinal tract is significantly weaker [13, 14]. The mechanism of action of NSAIDs is related to lower prostaglandin synthesis due to cyclooxygenase inhibition. Specifically, the conversion of arachidonic acid into cyclic endoperoxides, PGG2 and PGH2, from which prostaglandins PGE1, PGE2, PGF2α, and PGD2, prostacyclin PGI2, and thromboxanes is inhibited.(TxA2 and TxB2). Moreover, inhibition of prostaglandin synthesis may also affect inflammatory mediators, such as kinins, - thus direct effects are complemented by indirect effects.
The pain-relieving effect of dexketoprofen trometamol was determined through clinical trials using various pain models. In some study groups, the pain-relieving effect started 30 minutes after taking the medication. The pain-relieving effect lasts for 4-6 hours.

Dexketoprofen (Dolmen) and other NSAIDs
As mentioned, ketoprofen stands out for the strength of its analgesic effect, however, being a non-selective cyclooxygenase inhibitor, it can also cause similar side effects as other drugs in this class [13, 14].
Dexketoprofen is the water-soluble ketoprofen R-enantiomer salt, which inhibits cyclooxygenase 3,000 times more strongly than the S-enantiomer. Dexketoprofen is produced using innovative biotechnologies:
•    racemic ketoprofen is converted into the active form (ethyl ester);
•    a fungus Ophiostoma novo-ulmi-derived enzyme recognizes dexketoprofen in the racemic mixture;
•    the gene encoding the enzyme is identified by genetic engineering methods and cloned in the bacterium E. coli;
•    during dexketoprofen production, the purity of the final product is achieved at 99.9%.
Another stage in the production of Dolmen is the combination of dexketoprofen with trometamol. The trometamol salt improves the physical and chemical properties of dexketoprofen, the pharmacokinetics of the oral dosage form, and ensures a rapid and strong analgesic effect. Dexketoprofen trometamol easily dissolves in water and is well absorbed through the gastrointestinal mucosa. Dolmen contains 36.9 mg of dexketoprofen trometamol, equivalent to 25 mg of pure dexketoprofen. Treatment involves administering one Dolmen 25 mg tablet up to 3 times a day (daily dose - up to 75 mg). Food may slow down the absorption of dexketoprofen, so it is recommended to take this medicine 30 minutes before a meal.
Dexketoprofen inhibits prostaglandin production at the peripheral level, i.e. at the site of injury (trauma, inflammation, etc.), and at the central level (central nervous system). Therefore, dexketoprofen acts both as an anti-inflammatory and as a potent pain-relieving agent, characterized by rapid onset of action and better tolerability than its predecessor ketoprofen. Dexketoprofen effectively relieves acute nociceptive pain syndromes of various origins (associated with the activation of pain receptors), including musculoskeletal pain.
In a clinical study [15], the efficacy of Dolmen and tramadol was compared. 103 patients after orthopedic surgeries took 25 mg of dexketoprofen or 50 mg of tramadol for 3 days, and if needed, an additional 500 mg of paracetamol. Evaluating pain on the visual analog scale throughout the treatment period, especially the first 24 hours, it was found to constantly decrease. The onset of pain relief with both drugs was not different. In the first 60 minutes, dexketoprofen reduced pain by 60.85% from the baseline, while tramadol reduced it by 51.54%. The analgesic effect in both groups persisted for 72 hours after surgery, but the dexketoprofen group required less additional analgesics.
Treating 168 patients after lower limb orthopedic surgeries with 25 mg of dexketoprofen or 50 mg of tramadol every 6 hours for two days also revealed that the 25 mg dexketoprofen dose in the first 6 hours was more effective [16].
Comparing the analgesic effect of 25 mg of dexketoprofen with 500 mg of paracetamol and a combination of 22.5 mg of codeine, it was found that after hip joint transplantation, the need for morphine with both drugs was the same, and the analgesic effect was rated as "good" by an equal number of patients [17].
The pain-relieving effect of 25 mg of dexketoprofen and 50 mg of diclofenac was studied in 122 patients with acute foot trauma (65 received dexketoprofen and 57 received diclofenac) [18]. The groups did not significantly differ in terms of injury mechanisms, clinical symptoms, or average pain scores at the beginning of the study. Additional analgesia was needed for only 8 patients (5 in the diclofenac group, 3 in the dexketoprofen group, p = 0.32). No adverse drug effects were observed during the pain assessment period of 60 minutes.The decrease in the group of dexketoprofen was faster – it started to decrease after the first 15 minutes. Comparing the groups of diclofenac and dexketoprofen, it was found that the effect of dexketoprofen after 15, 30, 45, and 60 minutes exceeded the effect of diclofenac: respectively 0.53 (95% CI 0.03–1.09), 0.70 (95% CI 0.16–1.24), 0.89 (95% CI 0.32–1.47), and 0.83 (95% CI 0.21–1.45). The odds ratio for pain reduction by at least 1 point from the baseline (on an 11-point scale) after 15, 30, 45, and 60 minutes was respectively 2.66 (1.19–5.98), 3.52 (1.60–7.73), 4.48 (1.72–11.65), and 5.54 (1.90–16.15) for the benefit of dexketoprofen, and by 2 points or more – respectively 6.88 (1.48–32.0), 3.79 (1.59–9.01), 5.19 (2.29–11.78), and 5.87 (2.68–12.88).
The effectiveness of dexketoprofen in treating acute back pain was studied in 5 clinical double-blind randomized trials lasting about 1 week [19]. One study found that the effectiveness of treating with 50 mg of dexketoprofen twice a day is equivalent to 75 mg of diclofenac [19]. According to data from 4 other studies, the effectiveness of treatment for patients with acute severe or moderately severe back pain with 25 mg of dexketoprofen 3 times a day was the same as treating with 150 mg of diclofenac [20], 150 mg of tramadol [21], or 800 mg of paracetamol with 60 mg of dextropropoxyphene per day.
In the case of renal colic, the pain-relieving effect of injecting 50 mg of dexketoprofen trometamol into the muscles was the same as injecting 2000 mg of dipyrone, and when administered intravenously, 50 mg of dexketoprofen was the same as 100 mg of ketoprofen. The effect of dexketoprofen manifested faster than that of the other mentioned drugs [22].
The effectiveness of NSAIDs in treating pain caused by arthropathy was compared in two clinical double-blind randomized trials. The subjects took 25 mg of dexketoprofen 3 times a day or 150 mg of ketoprofen or 150 mg of diclofenac per day [23]. After 2–3 weeks of treatment, no difference was found between treatment with dexketoprofen and diclofenac, while treatment with ketoprofen was superior. The condition of patients treated with dexketoprofen improved by 75%, compared to only 50% of those treated with ketoprofen, and furthermore, there were fewer adverse events in the dexketoprofen group [23].

Summary
Pain is a current medical issue, and there is still no single drug suitable for everyone to treat it. Targeted treatment must be chosen in cases of both acute and chronic pain. NSAIDs remain the most important drugs for pain relief.
According to research data, the representative of this class of drugs, Dolmen, is as effective in relieving postoperative and acute lower back pain as tramadol, equivalent to twice the dose of its predecessor ketoprofen, and causes fewer unwanted gastrointestinal effects. Dexketoprofen can be combined with opioids to reduce their side effects.
Thus, it has been proven that dexketoprofen is an effective pain reliever with fewer side effects than its predecessor ketoprofen. Therefore, it is recommended for mild, moderate, and severe acute pain relief.

LT/Dol/2014/05

Literature
1. Consumer Reports Health Best Buy Drugs. The Nonsteroidal Anti-Inflammatory Drugs: Treating

2. Schlansky B., Hwang J.H.. Prevention of nonsteroidal anti-inflammatory drug-induced gastropathy. J Gastroenterol 2009; 44[Suppl XIX]:44–52;
3. Dooley M., Spencer C.M., Dunn Ch. J. Aceclofenac. A Reappraisal of its Use in the Management of Pain and Rheumatic Disease. Drugs 2001; 61 (9): 1351-1378;
4. Castellsague J., Riera-Guardia N., Calingaert B., Varas-Lorenzo C. et al. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project).; Safety of Non-Steroidal Anti-Inflammatory Drugs (SOS) Project. Source RTI Health Solutions, Barcelona, Spain.Drug Saf. 2012 Dec 1;35(12):1127-46.
5.    Roelofs PD, Deyo RA, Koes BW et al (2008) Non-steroidal anti-inflammatory drugs for low back pain. Cochrane Database Syst Rev(1): CD000396.
6.    Holdgate A & Pollock T (2004) Systematic review of the relative efficacy of non-steroidal anti-inflammatory drugs and opioids in the treatment of acute renal colic. BMJ 328(7453): 1401.
7.    Marjoribanks J, Proctor ML & Farquhar C (2003) Nonsteroidal anti-inflammatory drugs for primary dysmenorrhoea. Cochrane Database Syst Rev(4): CD001751.
8.    Derry C, Derry S, Moore RA et al (2009) Single dose oral ibuprofen for acute postoperative pain in adults. Cochrane Database Syst Rev(3): CD001548.
9.    Derry C, Derry S, Moore RA et al (2009) Single dose oral naproxen and naproxen sodium for acute postoperative pain in adults. Cochrane Database Syst Rev (1) CD004234.
10. Derry P, Derry S, Moore RA et al (2009) Single dose oral diclofenac for acute postoperative pain in adults. Cochrane Database Syst Rev(2): CD004768.
11. Marret E, Kurdi O, Zufferey P et al (2005) Effects of nonsteroidal antiinflammatory drugs on patientcontrolled analgesia morphine side effects: meta-analysis of randomized controlled trials. Anesthesiology 102(6): 1249–60.
12. Elia N, Lysakowski C & Tramer MR (2005) Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology 103(6): 1296–304.
13. Hernįndez-Dķaz S, Garcķa Rodrķguez LA (2000) Association Between Nonsteroidal Anti-inflammatory Drugs and Upper Gastrointestinal Tract Bleeding/Perforation: An Overview of Epidemiologic Studies Published in the 1990s. Arch Int Med, 160:2093-2099.
14. Laporte JR, Ibanez L, Vidal X, Vendrell L, Leone R (2004) Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents. Drug Saf. 27:411-420.
15. Schreiber M. Comparison of efficacy and tolerability of oral administration of 25 mg dexketoprofen trometamol versus tramadol 50 mg in patients with post-operative pain. Data on file. Menarini Pharmaceuticals.
16. A comparison of dexketoprofen trometamol 25 mg versus tramadol 50 mg in patients undergoing major orthopaedic surgey. Data on file. Menarini Pharmaceuticals.
17. Latarjet J. A comparative study on safety and efficacy of dexketoprofen trometamol versus paracetamol codeine in the treatment of moderate to severe pain in the post-operative follow-up of hip replacement surgery. Data on file. Menarini Pharmaceuticals.
18. Leman P, Kapadia Y, Herington J. Randomised controlled trial of the onset of analgesic efficacy of dexketoprofen and diclofenac in lower limb injury. Emerg Med J. 2003;20:511-513.
19. Zippel H, Wagenitz A. A multicentre, randomised, double-blind study comparing the efficacy and tolerability of intramuscular dexketoprofen versus diclofenac in the symptomatic treatment of acute low back pain. Clinical Drug Investigation 2007;27:533-543.
20. Granados J. Clinical trial to assess the efficacy and safety of LM-1158.tris (25 mg t.i.d) versus diclofenac (50 mg t.i.d) for the symptomatic treatment of patients with acute lumbar pain. Clinical Trial Report.
21. Kubler U. Comparative clinical trial of the efficacy and tolerability of 25 mg exketoprofen tid versus 50 mg tramadol tid in patients with acute lumbago of at least moderate severity. Clinical Trial Report 1999.
22. Sánchez-Carpena J, Domínguez-Hervella F, García I, et al. Dexketoprofen Renal Colic Study Group.Comparison of intravenous dexketoprofen and dipyrone in acute renal colic. European Journal of Clinical Pharmacology 2007;63:751-60.
23. Beltran J, Martin-Mola E, Figueroa M, et al. Comparison of dexketoprofen trometamol and ketoprofen in the treatment of osteoarthritis of the knee. Journal of Clinical Pharmacology 1998;38(12):74S-80S.