Aug 7, 1997 - Comparison with Intramuscular and Oral Piroxicam ... significant differences in efficacy between meloxicam and piroxicam. Local and overall.
Current Medical Kesearrh and Opirnow, Kd. 14, N o . 1 , 199729-38 0 I 9 9 7 Lihropharm Lirnired
Efficacy and Tolerability of Intramuscular and Oral Meloxicam in Patients with Acute Lumbago: A Comparison with Intramuscular and Oral Piroxicam Hans-Christoph Bosch*, Ralf Sigmund? and Marceline HettichS "TuttlingerStrasse 1, 0-78333 Stockach, Germany -fDr Karl Thomae, 0-88397 Biberach an der Riss, Germany
SBoehringer lngelheim GmbH, D-55216 Ingelheim, Germany Key words: Meloxicam - Piroxicam -Analgesic - Lumbago - COX-2 - Tolerability - Side-effects
Summary In this controlled, randomised, parallel-group, multicentre study, the efficacy and tolerability of an intramuscular ( i m ) dose of meloxicam (15 mg) on Day 1 followed by seven days of oral meloxicam (15 mglday) were compared with those of an i.m. dose of piroxicam (20mg) on Day 1 followed by seven days of oral piroxicam (20mglday) therapy in a total of 169 outpatients with acute lumbago. Time to onset of analgesic action after i.m. injection was determined, and overall efficacy, pain on movement, limitation of daily activities, local tolerability at the injection site and overall tolerability were assessed by investigators and patients on verbal rating scales (VRSs). Adverse events and laboratory assessments were documented. Meloxicam and piroxicam showed a rapid onset of action after i.m. injection (40 and 45 minutes median time, respectively), overall efficacy of both therapies was highly rated, and limitations to daily life were greatly reduced in the majority of patients in both groups. There were no statistically significant differences in efficacy between meloxicam and piroxicam. Local and overall tolerabilities were equally good for the two drugs, but there werefewergastrointestinal (GI) adverse events among meloxicam patients ( I .2% of patients) than piroxicam patients (7.0% of patients). The improved tolerability profile of meloxicam may be explained by its selectivity towards cyclooxygenase-2(COX-2).
Introduction Acute lumbago (low back pain) is very common, affecting millions of people each year. It has been estimated that in the UK alone 52.6 million certificated working days were lost in 1988-1989 as a result of l u m b a g o i 0 . The condition h a s h u g e economic implications in terms of lost o u t p u t a n d health-care costs. Acute lumbago usually results from excessive or unusual movement or strain of normal
structures in the lumbar vertebral column or from normal physical forces acting on abnormal structures2.'". The direct innervation of the lumbar region means that p a i n can b e caused by direct stimulation of local pain receptors. In addition, stimulation of spinal nerves causes inflammation a n d oedema, resulting in further nerve stimulation. Although acute lumbago is usually of short duration, typically resolving within two weeks, it is an extremely painful condition that demands rapid relief.
Addressfor correspondeme: Dr Hans-Christoph Bosch, Tuftlinger Strasse 1, D-78333 Stocltach, Germany. Fax: +49 77-716836 Accepted: 7th August 1997
7
Intramuscular and Oral Meloxicam in Patients with Acute Lumbago Hans-Chrisloph Bocch, Ralf Sigmund a n d Marceline Hettich
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat lumbago as they can provide long-lasting analgesia (through the night) without the risks associated with opiate analgesics.2,'o The anti-inflammatory action of NSAIDs is derived from their i n h i b i t i o n of cyclooxygenase (COX) activity and hence prostaglandin synthesis. There are at least two C O X isoforms. C O X - 1 , which mediates the cytoprotective and antithrombotic actions of prostaglandins, is constitutively expressed; thus it is present in most tissues at relatively constant concentrations . C 0 X - 2 , h o w ever, is induced in fibroblasts, macrophages and other cells by pro-inflammatory stimuli and cytokinesz6.The inhibition of COX- 1 is responsible for the gastrointestinal (GI) and renal side-effects of NSAIDs, so that those with selectivity for COX-2 should have fewer side-effects a n d be less irritating to the GI tractz5. Meloxicam is a new enolic acid-derived NSAID which has been shown to be effective in the treatment of rheumatoid arthritis (RA), arthrosis, sciatica and low back pain 1 . 6 . l 5 . 1 7 . 27 . Meloxicam is more selective for COX-2 over COX-1 than other NSAIDs5,s,9,20; and its improved tolerability and safety in comparison with NSAIDs such as piroxicam, diclofenac and naproxen, have been confirmed in clinical studies'. The aim of this study was to compare the efficacy (particularly in terms of the time to onset of analgesic action) and tolerability of intramuscular (i.m.) meloxicam followed by oral meloxicam with standard i.m. and oral piroxicam therapy in patients with acute lumbago.
Patients and Methods The study was a randomised, controlled, parallel-group trial, for which patients
were recruited from 12 centres. The study was carried out in accordance with the provisions of the Declaration of Helsinki; all patients gave informed written consent for participation. As the test medications differed in form, colour and volume, the study was conducted as an open clinical trial. Nevertheless, neither the physician nor the patient could recognise the medication group when following the study protocol correctly, as the test medications were packaged in opaque tubes. Thus, in spite of the different appearance of the two products, doubleblind conditions were, in reality, possible. For inclusion, patients had to be outpatients aged at least 18 years with acute lumbago of recent onset (within the previous 48 hours) resulting from muscular or skeletal tension or sprain of the lumbar spinal column. All patients had to have intermittent or constant pain between the spinal column, twelfth, posterior axillary line and gluteal fold. Exclusion criteria were: chronic or recurrent lumbago (more than two episodes in the preceding six months); pre-treatment or treatment of the most recent lumbago attack with muscle relaxants, spasmolytics, anxiolytics or physiotherapy; pre-treatment of the attack with NSAIDs or analgesics other than acetylsalicylic acid or paracetamol; clinical signs or symptoms of a disc prolapse; whiplash injury or direct trauma of the spinal column; clinical signs of an existing or k n o w n severe disease; clinical indications suggestive of a history of, or active, GI ulcer or haemorrhage during the preceding six months; clinical signs or history of coagulation disorders or tendency to haemorrhage; treatment with lithium or oral anti-coagulants; known hypersensitivity to analgesics, anti-pyretics or NSAIDs; participation in another clinical trial during the preceding four weeks or during the study. Pregnant or breast-feeding women a n d women
lntramuscnlar and Oral Meloxicam in Pafirnts with Acute Lumbago Hans-Christoph Bosch, Ralf Sigmund a n d Marceline Hettich
T t
31 without adequate contraception were also excluded. Patients were randomly assigned to receive i.m. meloxicam (15 mg) on Day 1 followed by oral meloxicam tablets (15 mg/ day) on Days 2-8 or i.m. piroxicam (20 mg) on Day 1 followed by oral piroxicam tablets (20mg/day) on Days 2-8. During the study, the patients were not to be given glucocorticoids, analgesics, other NSAIDs, muscle-relaxing agents, spasmolytics, anxiolytics or physiotherapy. Patients were assessed on Day 1 (Visit l),Day 2 (Visit 2) and at the end of the study (Visit 3 ) . The primary efficacy variables were time to onset of action after the i.m. dose (i.e., the time at which pain began to subside) and overall efficacy at the end of the study, as assessed by the investigator and patient on a four-point verbal rating scale (VRS) (very good, good, bad or very bad). For the endpoint ’time to onset of action’ the value of 12 hours was assigned for missing values or when the onset of action was longer than 12 hours. The secondary efficacy variables were pain on moving the lumbar region (before and after the injection at Visit 1, at Visit 2 and at the final visit) assessed by the investigator or patient on a five-point VRS (no, mild, moderate, severe or very severe pain), and limitation of daily activities (before treatment, at Visit 2 and at the end of the study) assessed by the patient on a fivepoint VRS (no, mild, moderate, severe or very severe limitation). At Visit 1 and at the end of the study, limitation of daily activities was also assessed using a modified version of a quality of life questionnaire3. For example, they were asked ‘could you now perform a regular activity in your profession/at home’ and ‘could you now sleep in a way that you feel fresh and rested?’. Overall tolerability was assessed by the investigator and patient at the end of the study and local tolerability at the injection
site was assessed at Visit 2. Both endpoints were assessed on a four-point VRS (very good, good, bad, very bad). Adverse events were recorded and classified as mild, moderate, severe or serious (classification as serious was according to the standard Case Report Form), and relationship to study medication was noted. Standard haematological and biochemical variables were assessed before treatment and at the final visit.
Statistical Analyses Sample size estimation was performed under the assumptions of a = 5 % and p = 10%. No adjustments of the significance level for multiple testing was required owing to an expected high correlation between the primary endpoints. Seventyfive evaluable patients for each treatment group was sufficient for finding a difference between the treatment groups of 5 5 % of the standard deviation in the endpoint ’time to onset of action‘. The results were analysed on an intentto-treat basis. The primary efficacy variables were evaluated using the Logrank test. The secondary efficacy variables were evaluated using a twosample t-test, U-test or chi-squared test, as appropriate.
Results Over the 12 centres, 169 patients were enrolled into the study and randomly assigned to receive treatment. There were no significant differences between the two groups at the onset of the study (Table 1). There were 12 premature discontinuations, seven in the meloxicam group (two owing to adverse events, two owing to insufficient
32 Table 1. Demographic characteristics (mean values f S.D.) of study patients Meloxicam ( n = 83)
Piroxicam ( n = 86)
48/35 47.1 (k 16.3) 173.7 (+ 8.6) 77.5 (k 13.6) 5.4 (k 14.6) 21.2 (+ 12.9)
53/33 46.3 (+ 15.5) 172.1 (i7.8) 77.7 (+ 12.8) 8.2 (i17.0) 20.2 (+ 13.4)
Male/female ( n ) Age (years) Height (cm) Weight (kg) *Broca2’(”/.) Time since onset o f lumbago attack (h) *Broca index = [weight/(height - 100) - 1) x 100
Table 2. Overall efficacy of meloxicam and piroxicam therapy in patients (percentage of group) as assessed by investigators and patients at the end of the study Investigator Meloxicam” Piroxicam Patient Meloxicam“ Piroxicam”
Very good
Good
Bad
Very bad
42 47
41 43
12 9
1 1
46 47
39 43
11 8
1 1
‘Ratings missing [or 3 patients. ”Rating missing for 1 patient.
efficacy a n d three for administrative reasons) and five in the piroxicam group (three owing to adverse events, one owing to insufficient efficacy a n d o n e for administrative reasons).
Primary Efficacy Variables Both meloxicam and piroxicam showed a rapid onset of action after i.m. injection, with median times of onset being 45 and 40 minutes, respectively. Overall efficacy was highly rated for both d r u g s by investigators and patients (Table 2), with more than 80% of investigators‘ and patients’ ratings of the overall efficacy of meloxicam and piroxicam being ’very good’ or ‘good’. There were no statistically significant differences between the two treatments for either endpoint.
Secondary Efficacy Variables More than 80% of the patients in both groups suffered severe to very severe pain
on movement before treatment on Day 1. Improvement was rapid in both groups (Figure 1); 90 minutes after injection, severe or very severe pain was reported by only 6% of meloxicam patients and 10% of piroxicam patients. There were no statistically significant differences between the two drugs in this parameter. Assessment of pain during movement at Visits 2 and 3 revealed no statistically significant differences between the two treatments ( F i g u r e 2 ) . A t t h e final assessment, 82% of the meloxicam group and 8 1 O/O of the piroxicam group had no, or only mild, pain. At the start of the study, 49% of patients in the meloxicam group and 52% of the piroxicam group suffered severe limitations to daily activities. At the end of the study, 5 3 % of meloxicam patients and 51% of piroxicam patients had no limitations. There were no statistically significant differences between the two treatments. The quality of life assessment (sum score of daily activities) improved similarly in the two groups from a mean score of 18 before treatment to 6 at the end of the study.
Intramuscular and Oral Meloxicam in Patients with Acute Lumbago Hans-Christoph Biisch, Ralf S i g m u n d a n d Marceline Hettich
33
Percent of patients
zz 1
After
15
rnin
45
Percent of patients
zi 1After 30 rnin
0Mcl(ix~carnI 5 mg* Pirirxicam 2 0 mg
45
25 20 15
None
Mild
xvere
SCVCIC
Pain during movement Percent of patients 55 50 45
After 60 rnin
0Mrloxicarri
1 5 rng*
Pimxicam 20 m g
-
Pain during movement
Percent of patients 50 - After 90 rnin 45 -
Pain during movement
0Mcloxicam
1 5 mg* Pirirxicam 20 mg
Pain during movement
+Percentages do not add up to 100 owing to rounding up/down and missing values "Ratings missing for two patients
Figure
1.
Pain during movement of the lumbar region after intramuscular injection of meloxicam or piroxicam as rated by patients (percentage of group)t
Tolerability There was a trend in favour of meloxicam with regard to local tolerability, which was rated by patients and investigators as 'very good' in 69% of patients, in comparison with corresponding ratings for piroxicam by patients and investigators of 59% and 64%, respectively. In both treatment groups, overall tolerability was rated by patients and investigators as 'very good' in the majority of patients (Figure 3 ) . There were no statistically significant differences between the two groups. In total, 2 4 different adverse events occurred in 18 patients (10.7%). In the
meloxicam group 11 different adverse events occurred in 8 patients (9.6% of the total n u m b e r of meloxicam-treated patients) and in the piroxicam group 13 different adverse events occurred in 10 patients ( l l . 6 ° / o ) . The incidence of GI disorders was six times higher in the piroxicam-treated group compared with the meloxicam-treated group (six versus one patient). The GI adverse events in the piroxicam-treated patients included abdominal pain, diarrhoea, dyspepsia and nausea. The GI adverse event in the meloxicam-treated patient was dyspepsia. The number of severe, moderate or mild adverse events was similar in both groups. None of the severe adverse events (which
lnrraniuscular and Oral iclel~xiian~ in Puiirnts with Arute L u m b q a Haiir-Chrirto[)h Rosch, Ralf Siernund and Marccline Herrich
34
Percent of patients 50
0Meloxicam
Day 2
1 5 mg ( n = 80)$
Piroxicam 20 mg (n = 86)
40 30 20
10 0
II None
I
Mild
I
Moderate
L Severe
I
Very severe
I
Pa n during movement
Percent of patients Meloxicam 15 mg (n = 74)" Piroxicam 20 mg (n= 79)**
40 30 -
20 10 0severe
Pain during movement tPercentages d o not add up to 100 owing to rounding up/down +Ratings missing for three patients "Ratings missing for nine patients **Ratings missing for seven patients
Figure 2. Pain during movement of the lumbar region on Day 2 and at the end of the study, as rated by patients (percentage of group)+
Inrrunzirsciiltir a n d Oi-ul Mrlmirunz i i i Patierits wiii? Acirre Lunzha,qo Hans-Cliristorili Boscli. Rall S i q m u n d a n d Marccline Hetticli
T 35
Percent of patients 70
1Investigator
60 50 40 30 20 100
1
4Very good '
Good
0Meloxicam
1 5 mg ( n = SO)*
H Piroxicam 20 mg (n = 84)**
I
Bad
I
Verybad
I
Overall tolerability
70- Patient
0Meloxicam
15 mg (n = 80)"
Piroxicam 20 mg (n = 83)*
60 50 40 30 20 10 0-l Very good I
Good
I
Bad
I
Verybad
I
Overall tolerability
+Percentages d o not add up to 100 owing to rounding up/down and missing values *Ratings missing for three patients **Ratings missing for two patients
Figure 3. Overall tolerability as assessed by investigators and patients at the end of the study (percentage of group)t
Intriimus~ularand Om/ Mrioxicam in Patients wirh Acute Lumbago Hans-ChristoDh Rosch. Ralf Sirinund arid Marcelinc Hettich
36 therapy is also equal to that of i.m. followed by oral piroxicam, with both drugs bringing good pain reduction and improving patients' ability to perform daily activities. The effectiveness of meloxicam in acute lumbago has previously been demonstrated i n a similar clinical trial in which intravenous meloxicam followed by oral therapy was compared with i.m. followed by oral diclofenac6. I n that study meloxicam was found to be significantly more effective and better tolerated than diclofenac6. In arthrosis and RA, i.m. meloxicam has been found to be more effective than i.m. p i r ~ x i c a m ' ~ . Local tolerability of i.m. piroxicam, although superior to that of diclofenac, can be poor, with injections causing burning, pain, redness and i n d ~ r a t i o n ~Poor , ~ ~local . tolerability can reduce compliance. Previous studies in patients with arthrosis and RA receiving multiple injections have found local tolerability of i.m. meloxicam to be superior to that of i.m. pir~xicam'~. Acute lumbago demands a treatment with Our study suggested that local tolerability a rapid onset of action. Intramuscular of meloxicam was better rated than that of injection of NSAIDs can provide more piroxicam, although the differences were rapid pain relief than oral administration, not statistically significant. However, the but may produce local irritation and study did confirm the excellent local of i.m. meloxicam found in necrosis a n d systemic ~ i d e - e f f e c t s ~ tolerability ~. Previous studies of the pharmacokinetics other studies in healthy v01unteers'~and and tolerability of i.m. meloxicam have in patients with acute lumbago6, arthrosis suggested that it is well absorbed and well and RAI3 and sciatica'. NSAIDs are highly effective drugs but tolerated and hence suitable for this i n d i ~ a t i o n ' ~In , ~patients ~. with sciatica, are associated with adverse effects, some treatment with i.m. injection of meloxicam of which, in particular those in the renal brought fast relief of induced pain and and GI systems, can be serious and lifetolerability was good'. Our study demon- threatening11,'2,14,L6,'8,23. Although the most strates that i.m. injection of meloxicam common GI side-effects - dyspepsia, 15 mg is an effective treatment for acute abdominal pain, nausea and diarrhoea lumbago, with a rapid onset of analgesic are not life-threatening, they are unpleasant action comparable to that of the standard and may reduce compliance. The more i.m. piroxicam therapy. Drug doses were serious GI side-effects, which include chosen on the basis of standard treatment perforation, ulceration and bleeding (PUB), for this disorder, so that results relevant to are a significant problem; NSAIDclinical practice could be obtained. Overall associated GI pathology accounts for 70 000 efficacy of i.m. injection followed by oral hospitalisations and 7000 deaths each year
were severe cases mainly of back pain) was related to treatment. In the piroxicamtreated group there were six cases of back pain. Three of these events led to discontinuation of therapy but none of these was related to treatment. In the meloxicam-treated group one patient reported pain at the end of the trial and there was one case of disc prolapse which was not related to treatment and did not result in discontinuation of therapy. None of the adverse events necessitated dosage reductions. There was a total of five discontinuations owing to an adverse event, three in the piroxicam-treated group and two in the meloxicam-treated group. There were no clinically relevant abnormal trends in laboratory variables related to the study medication in either group.
Discussion
Intramuscular a n d Oral Meloxicam in Parienrs with Acute Lunrbago Hans-Christoph Bo,ch, Ralr Sigmund a n d Marceline Hertich
37 in the USA”, and it has been estimated that NSAID users have a three-fold increased risk of developing serious GI adverse eventsI2.In our study, both meloxicam and piroxicam had good overall tolerability, but, as expected on the basis of its selectivity for COX-2 over COX-1, meloxicam was associated with approximately six times fewer GI adverse events than piroxicam. This finding is in agreement with a metaanalysis of double-blind clinical trials in arthrosis and RA patients which shows that the GI safety profile of meloxicam is superior to that of other NSAIDs7. In that meta-analysis, meloxicam at 7.5 mg and 1 5 mg doses w a s associated w i t h significantly fewer GI adverse events than piroxicam (20 mg), diclofenac (100 mg slow release) a n d naproxen (7501OOOmg). The incidence of severe GI adverse events associated with piroxicam or diclofenac was approximately three-fold greater than with either dose of meloxicam. In addition, there were significantly more PUBs in piroxicam 20mg and naproxen 750-1000 mg treated patients compared with both meloxicam treated groups. There were significantly more serious PUBs in the diclofenac 100 mg treated patients compared with the meloxicam 7.5 mg treated group.
Conclusions Meloxicam, given as an i.m. dose followed by oral treatment, is an effective and welltolerated treatment for acute lumbago. In terms of onset of action and overall efficacy, this meloxicam regimen is as effective as i.m. followed by oral piroxicam, but meloxicam showed a clear advantage over piroxicam in GI safety, with the incidence of GI adverse events being approximately six-fold greater in patients given piroxicam.
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