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

Pain Manage. (2011) 1(5), 409416

ISSN 1758-1869

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review WalczakDexketoprofen 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

O

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

review

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

0

1

2

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5

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8

9

10

11

12

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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review Walczakhad 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 (15mg/week) Hydantoines and sulfonamides Combinations to make with caution Diuretics, ACE inhibitors, angiotensinII receptor antagonists Methotrexate (