Review

Analgesic properties of dexketoprofentrometamol

Jean-Sbastien Walczak

Practice Points

Dexketoprofen trometamol is the dextrorotary (S)-(+) enantiomer of the NSAID ketoprofen formulated as a tromethamine salt. Dexketoprofen trometamol is available as oral tablets, oral solutions as granules, and parenteral formulation for intravenous and intramuscular injections. Dexketoprofen trometamol acts by inhibiting both cyclooxygenases1 and 2. The oral forms are indicated in the symptomatic treatment of pain of mild-to-moderate intensity while the parenteral form is indicated for acute pain of moderate-to-severe intensity. The recommended dosage is 12.5mg every 46h or 25mg every 8h without exceeding 75mg per day for the oral administration and 50mg every 812h or every 6h if necessary without exceeding 150mg for the parenteral formulation. Dexketoprofen trometamol appears as effective as the double dose of racemic mixture and other NSAIDs but with a faster onset of analgesia probably due to the tromethamine salt formulation. The adverse event profile of dexketoprofen appears similar to that of the new generation of NSAIDs. However, more long-term studies are needed to assess if dexketoprofen reduces the occurrence of adverse events compared with racemic ketoprofen.

Summary

Dexketoprofen trometamol is the dextrorotary enantiomer of the NSAID ketoprofen formulated as a tromethamine salt. The purpose of administering 50% of the racemic mixture is to keep the same analgesic and anti-inflammatory effect while reducing the adverse events due to both enantiomers. This article describes the pharmacological properties and evaluates the analgesic effects of dexketoprofen trometamol reported in acute and chronic pain conditions. The main conclusions are that dexketoprofen trometamol appears as effective as the double dose of the racemic drug. However, the reduction of adverse effects still has to be demonstrated. In addition, the formulation as tromethamine salt appears beneficial regarding fast onset of analgesia in acute painconditions.

Anesthesia Research Department & Alan Edwards Center for Research on Pain, McGill University, 3655 Promenade Sir William Osler, H3G 1Y6, Montral, Qubec, Canada; jsebwalczak@gmail.com

10.2217/PMT.11.42 2011 Future Medicine Ltd

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Dexketoprofen is the (S)-(+) enantiomer of ketoprofen, a chiral NSAID of the arylproprionate family (Figure1) . Racemic ketoprofen is one of the most potent inhibitors of prostaglandin synthesis and this affect appears to be mainly due to the (S)-(+)-ketoprofen while the (R)-(-)-ketoprofen is devoid of such activity [1,2] . The analgesic properties of the racemate are also only attributed to the (S)-(+)-ketoprofen enantiomer [3,4] . The rationale for using only the (S)-(+) enantiomer was to select the enantiomer having analgesic properties only, which would reduce the occurrence of adverse events due to both (S)-(+)- and (R)-(-)-ketoprofen. In addition, the metabolic and renal load would be reduced since the dosage represents 50% of ketoprofen [5] . Moreover, the tromethamine salt of dexketoprofen (dexketoprofen trometamol), which is used to increase the drug solubility also increases the absorption of dexketoprofen, therefore accelerating the onset of therapeutic effect [6] . indications & usage Dexketoprofen trometamol is recommended to treat mild-to-moderate pain conditions such as musculoskeletal pain (osteoarthritis, low back pain), dental pain and dysmenorrhea [7] . It is used as an analgesic and anti-inflammatory drug. The parenteral formulation is indicated for the symptomatic treatment of acute pain of moderateto-severe intensity, when oral administration is not appropriate, such as for postoperative pain, renal colic and low back pain. Dosage & administration The dosage given in this review will always be the equivalent of the amount of dexketoprofen. For example, 36.9 mg of dexketoprofen trometamol will correspond to 25 mg of dexketoprofen (see Figure1). In the UK, the recommended dosage is 12.5 mg every 46 h or 25 mg every 8 h without exceeding 75 mg per day. The treatment should be solely restricted to the symptomatic period [101] . The recommendations may vary between countries and are the same in all EU countries. The administration can be per os with a 25 mg dented tablet form, and, in 2002, a parenteral formulation was developed [8,9] . The recommended dose for parenteral administration is 50 mg every 812 h. If necessary, the administration can be repeated 6 h apart. The total daily dose should not exceed 150 mg. In cases of moderate-to-severe postoperative pain, parenteral dexketoprofen can be used in combination with opioid analgesics, as a part of a multimodal analgesia. Clinical pharmacology

Mechanism of action

OH O

MW = 254.28 g.mol1

The main mechanism of action of dexketoprofen, like other NSAIDs, is the inhibition of cyclooxygenases (COX), enzymes responsible for the synthesis of prostaglandins. In the racemic mixture of ketoprofen, this effect is mostly due to (S)-(+)-ketoprofen [1,2] .

Pharmacodynamics

HO

HO

NH2 HO

MW = 121.14 g.mol1

Dexketoprofen is an anti-inflammatory and antipyretic drug that inhibits COX-1 and -2. Clinical studies have shown an analgesic effect of dexketoprofen trometamol that lasted for 46 h and some reported analgesic activity after 30 min postadministration (see section Clinical evidence). In addition, a morphine sparing effect had been measured after parenteral administration of dexketoprofen in postoperative pain [10] .

Figure1. Dexketoprofen trometamol. (a) Ketoprofen and (B) trometamol. According to the MW, the quantity of dexketoprofen corresponds approximately to 67.7% of dexketoprofen trometamol dosage. Asymmetric carbon. MW: Molecular weight.

Pharmacokinetics Absorption

Dexketoprofen is highly lipophilic, therefore its absorption is controlled by the diffusion rate through the membranes and hydrophilic

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Analgesic properties of dexketoprofentrometamol compartments. After oral administration of dexketoprofen trometamol 37 mg (equivalent of 25 mg of dexketoprofen) to young healthy volunteers, tmax was approximately 30 min for a Cmax of 3.7 0.72 mg/l [6,11] . Interestingly, the absorption of the free acid form alone was delayed, which shows that tromethamine salt increased the absorption of dexketoprofen (see Figure2 ) [6] . The Cmax and t max values are approximately the same after intramuscular administration of the parenteral formulation [8] . Food or antacids do not impair the bioavailability of dexketoprofen trometamol (same area under the curve), but food increased tmax and reduced the Cmax [12] .
Distribution

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3.5 S-(+)-ketoprofen plasma concentration (mg/l) 3 2.5 2 1.5 1 0.5 0 Racemic ketoprofen 50 mg Dexketoprofen free acid 25 mg Dexketoprofen trometamol 25 mg

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Dexketoprofen is highly bound to plasma protein (99.2%). The apparent volume of distribution is in accordance with the binding to plasma protein, with 0.243 l/kg. The distribution halflife is of 0.35 h. In animal studies, (S)-(+)- and (R)-(-)-ketoprofen have both been detected in the synovial fluid following administration of the racemic drug [13,14] . Finally, dexketoprofen does not accumulate in fat tissue while the (R)-(-)-enantiomer does [13] .
Metabolism

Time post-dose (h)

Figure2. Mean plasma dexketoprofen concentrations after a single oral dose of dexketoprofen free acid 25mg, dexketoprofen trometamol 37mg (corresponding to 25mg of the acid) and racemic ketoprofen 50mg in 18 healthy volunteers. Note the faster absorption rate in the dexketoprofen trometamol group. Reproduced with permisison from [4].

Clinical evidence

Overview of clinical trials

Dexketoprofen trometamol is metabolized by the liver. The major metabolic pathways involve at least two cytochrome P450 enzymes (CYP2C8 and CYP2C9) [15] . Dexketoprofen trometamol has a number of metabolites, mainly hydroxyl derivatives [16] . In humans, however, hydroxylation plays a minor role. Dexketoprofen is mostly conjugated to an acyl-glucuronide. After administration of (S)-(+)-ketoprofen, the (R)-(-) enantiomer is not found in urine, demonstrating that there is no conversion from (S) to (R) in humans, while the opposite occurs at a low rate [13] .
Elimination

In a recent systematic review, Moore and Barden evaluated the analgesic effects of dexketoprofen in acute and chronic pain [17] . This review is strongly recommended to the reader who wants a fairly exhaustive review of the clinical trials with dexketoprofen.
Acute postsurgical pain

Dexketoprofen is eliminated by renal excretion after complete metabolism, no unchanged drug is found in the urine [16] . The elimination is rapid, after repeated administration (25-mg dexketoprofen three times a day) no accumulation could be detected [6,11] . The halflife (t1/2) and clearance (CL/F) have been reported to be 1.05 0.04 h and 0.089 0.004 l/h/kg in healthy subjects after a single dose of oral dexketoprofen trometamol [11] .

Oral dexketoprofen has been shown to relieve dental pain during a 46 h period following a first dose of 12.5, 25 or 50 mg for surgical removal of the third molar. No significant difference was observed between the 25- and 50-mg doses. The onset of analgesia was faster in the dexketoprofen groups (25 and 50 mg) compared with 50-mg ketoprofen [18] . Pre-emptive treatment did not increase the level of analgesia [1720] . In a recent review, using a number needed to treat (NNT) outcome, the equivalent efficacy of half doses of dexketoprofen compared with the racemic drug could not be demonstrated after a single oral dose of dexketoprofen in acute postsurgical pain [21] . However, the heterogeneity of the pain conditions and the small number of patients in the studies reviewed does not allow us to exclude formally that ketoprofen and dexketoprofen

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had an equivalent effect when using a 2:1 ratio [21] . The comparison with ketoprofen reached significance with a NNT of 8.8 when overall dexketoprofen 25- or 50-mg studies were compared with the double dose of ketoprofen 50or 100-mg studies [17] . In acute pain, combining third molar extraction and post surgical trials, after single dose, NNT for at least 50% pain relief are 3.5, 3.0 and 2.1 for 12.5, 25 and 50 mg dexketoprofen, respectively, compared with placebo [17] . It is in the range of other NSAIDs (e.g., naproxen 400 mg or diclofenac 50 mg) or paracetamol plus codeine [102] . Regarding parenteral administrations, recent studies showed that 50 mg dexketoprofen intravenous or intramuscular two or three times a day was as effective as 100 mg ketoprofen after hip or knee replacement surgery. The reduction of morphine consumption via a patientcontrolled analgesia administration system was significant compared with placebo [9,22] . After lumbar disc surgery, a recent randomized, double-blind, placebo-controlled study found that 50 mg dexketoprofen intravenous increased the latency of tramadol self-administration by patient-controlled analgesia. Moreover, the total consumption of tramadol was reduced as was the pain intensity measured by a visual analog scale (VAS). This reduction of opioid consumption could be linked to a decrease of side effects (nausea and vomiting) [23] . Finally, a single dose of dexketoprofen trometamol 50 mg intramuscular provided faster, better and longer duration of analgesia than diclofenac 50 mg with comparable safety in patients with hernia repair surgery [24] .
Other acute pain conditions

lasted for 6 h after administration. The onset of analgesia was faster with dexketoprofen 50 mg [26] . The same results were also obtained when dexketoprofen was administered intramuscularly and in patients with moderateto-severe pain due to renal colic [27] . In a study with a small number of patients, intramuscular injection of dexketoprofen 50 mg produced a better pain relief than diclofenac 75 mg intramuscular during a shockwave lithotripsy procedure in patients with renal or ureteral stones [28] . Doses of 12.5 and 25 mg dexketoprofen and 50 mg ketoprofen were compared with placebo in patients with dysmenorrhea. The three active drug groups produced a better pain relief than placebo with no significant difference amongst them. Interestingly, the group who received 12.5 mg dexketoprofen reported faster analgesia than the other ones [29,30] . Dexketoprofen 25 mg oral had the same effect as intrauterine lidocaine 2% on pain induced by uterine fractional curettage [31] . Finally, dexketoprofen did not reduce discomfort due to hysterioscopy in postmenopausal women on more than 2% mepivacaine but significantly reduced postoperative pain [32] .
Chronic pain conditions

Dexketoprofen 50 mg intramuscular twice daily has been evaluated in patients with acute low back pain. The pain scores measured during the 6 h after the first administration showed a reduction of pain similar to the one obtained with diclofenac 75-mg intramuscular [25] . Oral administration of dexketoprofen 25 mg threetimes daily over 47 days demonstrated a similar efficacy as diclofenac 150 mg, tramadol 150 mg and paracetamol (acetaminophen) 800 mg plus dextropropoxyphene 60 mg daily in acute low back pain [17] . An intravenous bolus of dexketoprofen 50 mg has been shown to relieve pain intensity in patients with renal colic. This effect was similar to dipyrone 50 mg intravenous and

Dexketoprofen has been evaluated against racemic ketoprofen in trials using multiple doses for osteoarthritis. In two studies, 25 mg dexketoprofen was compared with 50 mg ketoprofen [33] or to 50 mg diclofenac in patients with knee osteoarthritis [34] . Drugs were taken three times a day for 2 or 3 weeks. The first study measured a reduction of pain (using VAS) in both groups compared with baseline, and after 3 weeks the reduction of pain was significantly more important in the group having dexketoprofen. The evaluation of the condition by the physicians was also better in the dexketoprofen group [33] . In the second study, dexketoprofen reduced the pain and the severity of the disease assessed by the physician, but no significant difference was observed compared with diclofenac [34] . In patients with bone metastases, pain was reduced after administration of dexketoprofen 25 mg four times a day for 7 days and it was as effective as ketorolac 10 mg. Fewer adverse events were reported in the dexketoprofen group but the numbers were too small to reach statistical significance [35] .

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Analgesic properties of dexketoprofentrometamol Adverse reactions The recommended use of dexketoprofen is the same as with other NSAIDs, for which most common adverse reactions are gastrointestinal. Amongst these adverse events with NSAIDs, nausea and vomiting, diarrhea, abdominal pain and dyspepsia are common (110%). Gastritis, constipation, dry mouth and flatulence are uncommon (0.11%). Peptic ulcer, gastrointestinal bleeding or perforation are rare (0.010.1%) and pancreatitis very rare (<0.01%) [101] . Dexketoprofen has an incidence of upper gastrointestinal bleeding of 4.9%, which is lower than the older NSAIDs [36] . Although the gastrointestinal effects are the main adverse events with NSAIDs, the cardiovascular risks have to be taken into account when administering NSAIDs [37,38] . Safety studies with dexketoprofen on cardiovascular risks have to be performed even if after more than 15 years in the European market, no signal on this regard has been detected. Clinical trials on dexketoprofen demonstrated that after a single dose, the occurrence of adverse events is like ketoprofen as frequent as placebo treatments [21] . By definition, adverse events caused by drug withdrawal in clinical trials occurred for multiple doses. Any of the clinical trials reported serious adverse events such as gastrointestinal bleeding, myocardial infarction or death. Amongst 652 patients who received dexketoprofen for less than 2 days, 1.8% were withdrawn from treatment because of adverse reactions. The occurrence was 3.2% in 844 patients when the drug was administered for more than 2 days for example in low back pain or in osteoarthritis conditions [17,25,33,34] . A recent cohort study with 5429 patients who took dexketoprofen during 7 days for various pain conditions reported a similar occurrence (3.6%) of adverse events [39] . The duration of the trials performed so far (maximum 3 weeks) might explain the small number of adverse events reported. Studies using longer administration protocols have to be performed in order to assess the safety of long-term treatment with dexketoprofen. These will be crucial in order to validate the hypothesis that giving half the dose of ketoprofen by using only one enantiomer will successfully reduce adverse events. Finally, case reports of photodermatitis have been described in the literature after the use of oral dexketoprofen [40,41] . One case report of neutropenia, thrombocytopenia and liver damage has been mentioned recently [42] . Drug interactions Various types of interactions and associated risks may occur with the use of NSAIDs and therefore with dexketoprofen [101] . Interactions may involve the mechanism of action of dexketoprofen (inhibition of COX enzymes) or the metabolic load. See Table1 for details. Use in specific populations

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Children & adolescents

No evaluation of dexketoprofen regarding safety and efficacy has been performed in children or adolescents. Therefore, it is not recommended to use this drug in such a population.

elderly

After administration of single (25 mg) or multiple doses (25 mg, three times a day for 3 days) of dexketoprofen trometamol in healthy elderly subjects, the elimination was decreased in comparison with young patients. This might be due to the decline of renal function in elderly patients. However, no accumulation could be observed [11] . It is recommended to reduce the maximal daily dose to 50 mg [101] .

Pregnancy: lactation period

No data have been collected with dexketoprofen. However, as with other NSAIDs, the use of dexketoprofen during pregnancy is contraindicated. Also, this drug may decrease female fertility and is not recommended for women who are trying to conceive [101] . Regarding the lactation period, ketoprofen has been found in milk of women treated for maternal pain after delivery [43] . It is therefore highly probable that the same phenomenon occurs for dexketoprofen.

impaired liver function

Dexketoprofen is not recommended for patients with severe liver function impairment (class C in the ChildPugh score). A recent pharmacokinetic study in patients with class A or B (ChildPugh) hepatic impairment scores showed a reduced excretion of conjugated dexketoprofen mostly for class B patients compared with healthy patients, although this was not statistically significant [44] . Adjustment of the dose is recommended for patients with impaired hepatic function.

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Table1. Drug interactions with NSAiDs applicable to dexketoprofen.
Class inadvisable combinations Other NSAIDs and corticosteroids Anticoagulants (warfarin orheparins) Lithium Methotrexate (>15mg/week) Hydantoines and sulfonamides Combinations to make with caution Diuretics, ACE inhibitors, angiotensinII receptor antagonists Methotrexate (<15mg/week) Pentoxifilline Sulfonylureas Zidovudine b-blockers Cyclosporin and tacrolimus Thrombolytics Antiplatelet agents and SSRIs Probenecid Cardiac glycosides Mefepristone Quinolones Increased deterioration of renal function in patients at risk (dehydrated, elderly) Increased risk of hematological toxicity Increased risk of bleeding Increased hypoglycemic effect Increased red cell line toxicity Possible decrease of the antihypertensive effect Nephrotoxicity of those drugs may beenhanced Increased risk of bleeding Increased risk of gastrointestinal bleeding Possible increased plasma concentration ofdexketoprofen Possible increased plasma concentration Possible alteration of the effect Possible convulsions (observed in animals) Reduction of the diuretic effect Decreased renal clearance Inhibition of platelet function Displacement of plasma protein Action on reticulocytes Inhibition of prostaglandin synthesis Inhibition of renal prostaglandins Inhibition of platelet function Synergistic effect on gastrointestinal damage Inhibitory mechanism at the site of renal tubularexcretion N/A Diminution of prostaglandins N/A Gastointestinal ulcers and bleeding Increased hemorrhage Synergistic effect Inhibition of platelet function, damage to gastrointestinal mucosa, warfarin binding on plasma protein might be displaced Decreased renal excretion of lithium Decreased renal clearance N/A Risk Mechanism

Lithium reaches toxic concentration Hematological toxicity Increased toxicity

Combinations to be taken into account

ACE: Angiotensin converting enzyme; N/A: Not applicable; SSRI: Selective serotonin reuptake inhibitor. Data taken from [101].

Renal failure

In patients with mild and moderate chronic renal insufficiency the cumulative (during 24 h) excretion of conjugated dexketoprofen in urine is decreased compared with healthy patients after a single administration of 12.5 mg dexketoprofen trometamol. The other pharmacokinetic parameters (t max, area under the curve, clearance, volume of distribution) were unchanged [45] . The dose of dexketoprofen should be adjusted to 50 mg daily in patients with mildly impaired renal function (stage 1 and 2) and should not be used in patients with moderate-to-severe renal dysfunction (stage 3 and 4) [101] . Conclusion & future perspective In acute pain, dexketoprofen appears to be as effective as the racemic ketoprofen and other NSAIDs. However, the rapid absorption due to the tromethamine salt might be beneficial for a rapid onset of the analgesic effect. Yet,

the rationale for reducing the dose compared with ketoprofen is hard to verify in acute pain for single dose. Indeed, adverse effects are as frequent as placebo because the drug is used for a short period of time. The studies evaluating multiple administrations of dexketoprofen were for a maximum duration of 3 weeks and reported adverse events similar to ketoprofen. However, further studies using long treatment have to be performed in order to assess the safety of long-term treatment with dexketoprofen. It will be important to validate the hypothesis that administering half the dose of ketoprofen by using only one enantiomer will successfully reduce adverse events compared with the racemic mixture.
Acknowledgements
The author thanks P Beaulieu for giving his advice regarding the practice point section and for his critical reading of the manuscript.

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Analgesic properties of dexketoprofentrometamol

Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t estimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Rodriguez MJ, Arbos RM, Amaro SR. Dexketoprofen trometamol: clinical evidence supporting its role as a painkiller. Expert Rev. Neurother. 8(11), 16251640 (2008). Valles J, Artigas R, Bertolotti M et al. Single and repeated dose pharmacokinetics of dexketoprofen trometamol in young and elderly subjects. Methods Find. Exp. Clin. Pharmacol. 28(Suppl. A), 1319 (2006). McEwen J, De Luca M, Casini A et al. The effect of food and an antacid on the bioavailability of dexketoprofen trometamol. J. Clin. Pharmacol. 38(Suppl. 12), 41S45S (1998). Barbanoj MJ, Antonijoan RM, Gich I. Clinical pharmacokinetics of dexketoprofen. Clin. Pharmacokinet. 40(4), 245262 (2001). Good review on the pharmacokinetic properties of dexketoprofen compared with dexketoprofen. Jamali F, Brocks DR. Clinical pharmacokinetics of ketoprofen and its enantiomers. Clin. Pharmacokinet. 19(3), 197217 (1990). Martinez C, Blanco G, Ladero JM et al. Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use. Br. J. Pharmacol. 141(2), 205208 (2004). Sweetman BJ. Development and use of the quick acting chiral NSAID dexketoprofen trometamol (Keral). Acute Pain 4, 109115 (2003). Moore R A, Barden J. Systematic review of dexketoprofen in acute and chronic pain. BMC Clin. Pharmacol. 8, 11 (2008). Excellent exhaustive systematic review on clinical trials with dexketoprofen for the treatment of acute and chronic pain. McGurk M, Robinson P, Rajayogeswaran V et al. Clinical comparison of dexketoprofen trometamol, ketoprofen, and placebo in postoperative dental pain. J. Clin. Pharmacol. 38(Suppl. 12), 46S54S (1998). Jackson ID, Heidemann BH, Wilson J, Power I, Brown RD. Double-blind, randomized, placebo-controlled trial comparing rofecoxib with dexketoprofen trometamol in surgical dentistry. Br. J. Anaesth. 92(5), 675680 (2004).
26 25 20

review

Bibliography
Papers of special note have been highlighted as: of interest of considerable interest

10

Hayball PJ, Nation RL, Bochner F. Enantioselective pharmacodynamics of the nonsteroidal antiinflammatory drug ketoprofen: in vitro inhibition of human platelet cyclooxygenase activity. Chirality 4(8), 484487 (1992). Hardikar MS. Chiral non-steroidal antiinflammatory drugs a review. J. Indian Med. Assoc. 106(9), 615618, 622, 624 (2008). Cabre F, Fernandez MF, Calvo L, Ferrer X, Garcia ML, Mauleon D. Analgesic, antiinflammatory, and antipyretic effects of S(+)-ketoprofen in vivo. J. Clin. Pharmacol. 38(Suppl. 12), 3S10S (1998). Mauleon D, Artigas R, Garcia ML, Carganico G. Preclinical and clinical development of dexketoprofen. Drugs 52(Suppl. 5), 2445 (1996). Wechter WJ. Dexketoprofen trometamol. J. Clin. Pharmacol. 38(Suppl. 12), 1S2S (1998). Barbanoj MJ, Gich I, Artigas R et al. Pharmacokinetics of dexketoprofen trometamol in healthy volunteers after single and repeated oral doses. J. Clin. Pharmacol. 38(Suppl. 12), 33S40S (1998). Sweetman BJ. Development and use of the quick acting chiral NSAID dexketoprofen trometamol (Keral). Acute Pain 4(3), 109115 (2003). Valles J, Artigas R, Crea A et al. Clinical pharmacokinetics of parenteral dexketoprofen trometamol in healthy subjects. Methods Find. Exp. Clin. Pharmacol. 28(Suppl. A), 712 (2006). Interesting recent pharmacokinetics data regarding elderly subjects. Zippel H, Wagenitz A. Comparison of the efficacy and safety of intravenously administered dexketoprofen trometamol and ketoprofen in the management of pain after orthopaedic surgery: a multicentre, doubleblind, randomised, parallel-group clinical trial. Clin. Drug Investig. 26(9), 517528 (2006).

11

Jimenez-Martinez E, Gasco-Garcia C, Arrieta-Blanco JJ, Gomez del Torno J, Bartolome Villar B. Study of the analgesic efficacy of dexketoprofen trometamol 25mg. vs. ibuprofen 600 mg. after their administration in patients subjected to oral surgery. Med. Oral 9(2), 138143 (2004). Barden J, Derry S, McQuay HJ, Moore R A. Single dose oral ketoprofen and dexketoprofen for acute postoperative pain in adults. Cochrane Database Syst. Rev. 4, CD007355 (2009). Focuses on dexketoprofen on acute pain trials and provides the calculation of numbers needed to treat. Hanna MH, Elliott KM, Stuart-Taylor ME, Roberts DR, Buggy D, Arthurs GJ. Comparative study of analgesic efficacy and morphine-sparing effect of intramuscular dexketoprofen trometamol with ketoprofen or placebo after major orthopaedic surgery. Br J. Clin. Pharmacol. 55(2), 126133 (2003). Yazar MA, Inan N, Ceyhan A, Sut E, Dikmen B. Postoperative analgesic efficacy of intravenous dexketoprofen in lumbar disc surgery. J. Neurosurg. Anesthesiol. 23(3), 193197 (2011). Jamdade PT, Porwal A, Shinde JV et al. Efficacy and tolerability of intramuscular dexketoprofen in postoperative pain management following hernia repair surgery. Anesthesiol. Res. Pract. 2011, 579038 (2011). 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. Clin. Drug Investig. 27(8), 533543 (2007). Sanchez-Carpena J, Dominguez-Hervella F, Garcia I et al. Comparison of intravenous dexketoprofen and dipyrone in acute renal colic. Eur J. Clin. Pharmacol. 63(8), 751 760 (2007). Sanchez-Carpena J, Sesma-Sanchez J, Sanchez-Juan C et al. Comparison of dexketoprofen trometamol and dipyrone in the treatment of renal colic. Clin. Drug Investig. 139152 (2003).

21

12

13

22

14

23

15

24

16

17

18

19

27

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review Walczak
28

Tokgoz H, Yurtlu S, Hanci V et al. Comparison of the analgesic effects of dexketoprofen and diclofenac during shockwave lithotripsy: a randomized, doubleblind clinical trial. J. Endourol. 24(6), 10311035 (2010). Ezcurdia M, Cortejoso FJ, Lanzn R et al. Comparison of the efficacy and tolerability of dexketoprofen and ketoprofen in the treatment of primary dysmenorrhea. J. Clin. Pharmacol. 38(Suppl. 12), 65S73S (1998). Balani M, Gawade P, Maheshgauri S, Ghole S, Shinde V, Sathe V. Results of two multicentric, comparative, randomized, parallel group clinical trials to evaluate the efficacy and safety of dexketoprofen trometamol in the treatment of dental pain and dysmenorrhoea in Indian patients. J. Clin. Diagn. Res. 2(5), 10861091 (2008). Api O, Ergen B, Api M, Ugurel V, Emeksiz MB, Unal O. Comparison of oral nonsteroidal analgesic and intrauterine local anesthetic for pain relief in uterine fractional curettage: a randomized, double-blind, placebo-controlled trial. Am. J. Obstet. Gynecol. 203(1), e21e27 (2010). Mercorio F, De Simone R, Landi P, Sarchianaki A, Tessitore G, Nappi C. Oral dexketoprofen for pain treatment during diagnostic hysteroscopy in postmenopausal women. Maturitas 43(4), 277281 (2002). Beltran J, Martin-Mola E, Figueroa M et al. Comparison of dexketoprofen trometamol and ketoprofen in the treatment of osteoarthritis of the knee. J. Clin. Pharmacol. 38(Suppl. 12), 74S80S (1998). Marenco JL, Perez M, Navarro FJ et al. A multicentre, randomised, double-blind study to compare the efficacy and tolerability of

dexketoprofen trometamol versus diclofenac in the symptomatic treatment of knee osteoarthritis. Clin. Drug Investig. 19, 247256 (2000).
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42

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Rodriguez MJ, Contreras D, Galvez R et al. Double-blind evaluation of short-term analgesic efficacy of orally administered dexketoprofen trometamol and ketorolac in bone cancer pain. Pain 104(12), 103110 (2003). Laporte JR, Ibanez L, Vidal X, Vendrell L, Leone R. Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents. Drug Saf. 27(6), 411420 (2004). Trelle S, Reichenbach S, Wandel S et al. Cardiovascular safety of non-steroidal antiinflammatory drugs: network meta-ana lysis. BMJ 342, c7086 (2011). Ritter JM, Harding I, Warren JB. Precaution, cyclooxygenase inhibition, and cardiovascular risk. Trends Pharmacol. Sci. 30(10), 503508 (2009). Carne X, Rios J, Torres F. Postmarketing cohort study to assess the safety profile of oral dexketoprofen trometamol for mild to moderate acute pain treatment in primary care. Methods Find. Exp. Clin. Pharmacol. 31(8), 533540 (2009). Asensio T, Sanchis ME, Sanchez P, Vega JM, Garcia JC. Photocontact dermatitis because of oral dexketoprofen. Contact Dermatitis 58(1), 5960 (2008). Goday-Bujan JJ, Rodriguez-Lozano J, Martinez-Gonzalez MC, Fonseca E. Photoallergic contact dermatitis from dexketoprofen: study of 6 cases. Contact Dermatitis 55(1), 5961 (2006).

Zabala S, Calpe MJ, Perez G, Lerin FJ, Mouronval L. Neutropenia, thrombocytopenia and hepatic injury associated with dexketoprofen trometamol therapy in a previously healthy 35-year-old woman. J. Clin. Pharm. Ther. 33(1), 7981 (2008). Jacqz-Aigrain E, Serreau R, Boissinot C et al. Excretion of ketoprofen and nalbuphine in human milk during treatment of maternal pain after delivery. Ther. Drug Monit. 29(6), 815818 (2007). Valles J, Artigas R, Bertolotti M et al. Single and repeated dose pharmacokinetics of dexketoprofen trometamol in patients with impaired liver function. Methods Find. Exp. Clin. Pharmacol. 28(Suppl. A), 2936 (2006). Interesting recent pharmacokinetics data regarding patients with diminished liver function. Valles J, Artigas R, Mas M et al. Pharmacokinetics of dexketoprofen trometamol in subjects with mild and moderate chronic renal insufficiency. Methods Find. Exp. Clin. Pharmacol. 28(Suppl. A), 2128 (2006). Interesting recent pharmacokinetics data regarding patients with renal failure.

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websites
Keral (2011) www.medicines.org.uk/EMC/ medicine/17099/SPC/Keral/#POSOLOGY

101 The electronic Medicines Compendium

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102 Oxford league table of analgesics in

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acute pain www.medicine.ox.ac.uk/bandolier/booth/ painpag/Acutrev/Analgesics/Leagtab.html

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Pain Manage. (2011) 1(5)

future science group