Download tolerabiijty of multiple administration of intramuscular meloxicam

British Journal of Rheumatology 1996;35(suppL l):51-55
TOLERABIIJTY OF MULTIPLE ADMINISTRATION OF
INTRAMUSCULAR MELOXICAM: A COMPARISON WITH
INTRAMUSCULAR PIROXICAM IN PATIENTS WITH RHEUMATOID
ARTHRITIS OR OSTEOARTHRITIS
P. R. GHOZLAN,* M. BERNHARDT,f P. VtUCTTATt and E. BLUHMKI§
*Polydiniqued'Aubervilliers, 55 Henri Barbusse, 93308 Aubervillien Cidex, France, fKurklinikamPark. Berliner
Strasse9,59505 BadSassendorf, Germany.}BoehringerIngelheim France, 12 rue Andre Huet, BP292,51060
Reims Cidex, France and § Boehringer Ingelheim GmbH, BirkendorferStrasse65,88397 BiberachlRiss, Germany
SUMMARY
This multicentre, randomized, open controlled study compared the local and overall tolerability of i.m. meloxicam with i.m.
piroxicam in 211 patients with rheumatoid arthritis (RA) (n = 95) or osteoarthritis (OA) (n = 116). Of these, 210 patients were
randomized (2:1) to receive meloxicam 15 mg (u = 144) or piroxicam 20 mg (n = 66) for 7 days. Local tolerability of meloxicam was
significantly better than piroxicam with respect to occurrence of redness after the first injection (P = 0.03) and global assessment
after the first and final injections (P < 0.05). No rise in creatinine phospholcinase levels (a marker of muscle fibre damage) was
observed with meloxicam, in contrast to piroxicam (P = 0.0001). The overall tolerability of both treatments was good. Significant
differences in favour of meloxicam were observed for global efficacy assessed by the patient in RA (P < 0.05) and for overall pain
intensity in OA patients (P = 0.02). In conclusion, i.m. meloxicam is safe and effective for the treatment of acute rheumatic pain and
shows some superiority over piroxicam.
Meloxicam, Piroxicam, Tolerability, Intramuscular, Osteoarthritis, Rheumatoid arthritis, Non-steroidal
anti-inflammatory drugs, Creatinine phosphokinase.
KEY WORDS:
non-steroidal anti-inflammatory drug
(NSAID) formulations are used in some centres for the
treatment of acute rheumatoid and osteoarthritis (RA
and OA). They are especially useful for the treatment of
patients who experience difficulties in taking oral
formulations. In these patients an i.m. NSAID with a
rapid onset of action and good local and overall
tolerability is required. However, many NSAIDs are
poorly tolerated when administered via the i.m. route,
resulting in local tissue irritation and necrosis, often in
association with systemic adverse events. Clinical
evidence indicates that meloxicam is associated with a
favourable gastrointestinal (GI) safety profile [1], and
large phase III studies with oral formulations have
revealed good efficacy and tolerability in a range of
rheumatic conditions including OA [2, 3] and RA [4, 5].
Intramuscular meloxicam (5-30 mg) has previously
been shown to be well tolerated, with maximum plasma
levels achieved within 1 h of dosing compared to 6-8 h
after oral dosing [6\. There is also a linear relationship
between plasma concentration and dose [6].
The aim of the present study was to compare the
local and overall tolerability of i.m. meloxicam 15
mg/day with i.m. piroxicam 20 mg/day—a standard
NSAID with proven efficacy and safety—in patients
with OA or RA.
on American Rheumatism Association [ARA] criteria)
[7] or OA of the hip (American College of Rheumatology criteria) [8] or knee (ARA criteria) [9] were
enrolled in this multicentre, randomized, open controlled study conducted in France and Germany. The
following criteria were used to exclude patients: if they
had taken NSAIDs during the last 1-3 days (depending
upon the half-life of the drug taken); any i.m. injection
within the last 48 h; any contraindication to i.m.
injections; a hip prosthesis or might receive one within
6 months; a skin infection which could interfere with
assessment of local tolerability; pregnancy or lactation;
severe renal, hepatic, cardiac, metabolic or haematological disease; cancer; mental disturbance; ulcerative
colitis; asthma; active peptic ulceration or other gastric
complaints within the last 2 weeks; adverse events due
to an NSAID (not yet recovered); hypersensitivity to
analgesics, antipyretics and NSAIDs; treatment with
anticoagulants, lithium or hydantoins; inclusion in
another clinical trial in the last month.
INTRAMUSCUIAR
Study design
Following an initial assessment, patients were
randomly assigned (2:1) to treatment with i.m.
meloxicam 15 mg or i.m. piroxicam 20 mg once daily for
7 days. The drugs were injected into the buttock using
normal aseptic techniques. As the colour and volume of
the meloxicam ampoules (1.5 ml) differed from that of
the piroxicam ampoules (1 ml), the study could not be
conducted according to a double-blind design.
All patients kept a daily diary during treatment.
Additionally, they were assessed by the clinician on two
occasions, the first within 15 min of the first injection
PATIENTS AND METHODS
Patients
Patients, aged between 18 and 75 yr, with RA (based
Correspondence to: P. Vilicitat, Boehringer IngeJhcim France, 12
rue Andre Huet, BP 292, 51060 Rams Cidex, France.
O 1996 British Society for Rheumatology
51
52
STUDIES ON MELOXICAM (MOBIQ
TABLE I
Comparability of treatment groups at inclusion
OA stratum (n = 115)
RA stratum (n = 95)
Total(n = 210)
Meloxicam
Piroxicam
Meloxicam
Piroxicam
Meloxicam
Piroxicam
76
39
68
27
144
66
50 (65.8)
26 (34.2)
25(64.1)
14 (35.9)
50(73.5)
18(26.5)
25 (92.6)
2(7.4)
100 (69.4)
44(30.6)
50 (75.8)
16 (24.2)
Mean (± S.EJH.) age (yr)
61.811.2
Mean (± S.EJ4.) body
76.2 ±1.5
weight (kg)
Mean (± itM.) body
164.1 ±1.0
height (cm)
Mean (± S.EM.) duration
knee: 5.3 ± 0.5
of disease (yr)
hip: 6.8 ±1.5
Mean (± S.EJH.) overall
60.6 ± 2.0
pain intensity at baseline
(mmVAS)
60.6 ± 1.6
80.6 ± 2.4
55.5 ± 1.3
67.8 ± 1.5
55.9 ±1.8
622 ± 2.0
58.8 ±0.9
72.3 ±1.1
58.711.2
73.112.0
166.2 ±1.4
164.4 ±0.9
161.1 ±1.5
164.3 ±0.7
164.111.1
knee: 7.8 ±1.1
hip: 4.6 ±1.2
58.4 ±2.3
7.8 ±1.1
6.1 ±1.3
63.4 ± 2.6
56.6 ± 4.7
61.9 ±1.6
57.6 1 2.3
No. of patients
Sex; n (%)
Female
Male
and the second 24 h after the last injection. The primary
endpoint was the local tolerability of the injections
as assessed by the patient and the clinician. Local
tolerability was assessed daily by the patient within 1 h
of injection on a four-point verbal rating scale (very
good, rather good, rather bad, very bad). Local
tolerability was assessed by the clinician by recording
absence or presence of reddening, swelling, heat or pain
on pressure at the site of injection. A global assessment
of local tolerability was recorded by the clinician on the
same four-point verbal rating scale as the patient
Secondary endpoints included overall tolerability,
assessed by the patient and the clinician on the same
four-point verbal rating scale as above. Other
tolerability endpoints included the rate of withdrawals
due to safety reasons; the number, nature and severity
of adverse events; creatinine phosphokinase (CPK)
levels; and other laboratory investigations. Efficacy
endpoints included global efficacy assessed by the
patient and clinician at the second visit on the
four-point verbal rating scale; overall pain intensity as
assessed by the patient before drug administration and
at the second visit on a 100 mm visual analogue scale
(0 mm = no pain, 100 mm = unbearable pain); and the
consumption of paracetamol.
Statistical methods
The confidence intervals for local tolerability, overall
tolerability and overall efficacy were calculated.
Treatment differences were determined using Fisher's
exact test. A two-sample f-test was performed on the
assessment of pain intensity. Since the normal ranges
were not identical for all the laboratories taking part in
this multicentre study, the analysis of laboratory
parameters was based on transformed values. Changes
in laboratory parameters from baseline to the final
assessment (transformed values) were evaluated descriptively. Tests were considered significant if P £ 0.05.
A sample size of 200 patients was chosen to collect
sufficient safety data especially for local tolerability
assessment.
• Meloxicam
• Piroxicam
Reddening
Swelling
Heat
Pain on
pressure
Fio. 1.—Clinicians' assessment of local tolerability after the first injection of meloxicam or piroxicam.
GHOZLAN ETAL: TOLERABI1JTY OF INTRAMUSCULAR MELOXICAM
Reddening
Swelling
Heat
I
Meloxicam
•
Piroxicam
53
Pain on
pressure
Fio. 2.—Clinicians' assessment of local tolerability after the final injection of meloxicam or piroxicam.
RESULTS
The demographic data are shown in Table I. One
patient was withdrawn before receiving the first
injection due to depression and was not analysed. There
was a tendency for the duration of knee OA to be longer
in the piroxicam group than in patients treated with
meloxicam (P = 0.06). The groups were well matched in
all other parameters.
Primary endpoints
Evaluation of local tolerability by the clinician
revealed excellent results for both meloxicam and
piroxicam, although meloxicam treatment offered an
advantage that was statistically significant for a number
of parameters. After the first injection, local reddening,
swelling, heat and pain on pressure were all observed in
more patients in the piroxicam group than in the
meloxicam group, the difference achieving statistical
significance with respect to local reddening (9.1% vs
2.1%; P = 0.03) (Fig. 1). Similarly, global local tolerability as assessed by the physician revealed a statistically
significant advantage for meloxicam over piroxicam
(P = 0.045); treatment was considered 'very good' in
134/144 (93.1%) patients treated with meloxicam and in
55/66 (83.3%) treated with piroxicam. Twenty-four
hours after the final injection, patients in the meloxicam
group experienced less reddening, swelling, beat and
pain on pressure than those in the piroxicam group,
although none of the differences achieved statistical
significance (Fig. 2). The global local tolerability
assessments were more significant with meloxicam than
with piroxicam (P = 0.029). Global local tolerability
was rated as 'very good' in 130/144 (90.3%) patients
treated with meloxicam and in 52/66 (78.8%) of those
treated with piroxicam.
Local tolerability assessments recorded by the
patients in a daily diary and 24 h after the final injection
showed similarly good results for both meloxicam and
piroxicam; 24 h after the final injection, local tolerability was rated as 'very good' by 121/144 (84.0%)
TABLEn
Changes in CPK levels from baseline to the final visit following
treatment with meloxicam or piroxicam
Meloxicam
(n =131)
Piroxicam
(n = 62)
P-vahw
(between groups)
Increase of at
47 (35.9%)
40 (64.5%)
0.0005
Increase of at
least 10IU/1
Increase of at
least 20 IU/1
Increase of at
least 30 IU/1
26(19.9%)
25 (40.3%)
0.005
9 (6.9%)
18 (29.0%)
0.0001
5(3.8%)
14 (22.6%)
0.0001
!„,< i ni/i
patients receiving meloxicam and by 53/66 (80.3%)
receiving piroxicam.
Secondary endpoints
Safety. Both drugs showed good overall tolerability as
assessed by the clinician and the patients. The clinicians
rated overall tolerability as 'very good' in 121/144
(84.0%) patients in the meloxicam group and 55/66
(83.3%) in the piroxicam group. The corresponding
assessment by the patients revealed 'very good' overall
tolerability in 117/144 (81.2%) patients treated with
meloxicam and 53/66 (80.3%) treated with piroxicam.
Muscular tolerability, determined by changes in
serum CPK from baseline to after the final injection,
was significantly better with meloxicam than with
piroxicam (P = 0.0001). Indeed, there was no mean
change in CPK levels in the meloxicam group (0%),
while the piroxicam group was associated with a
statistically significant increase (59%) from baseline
(P= 0.01). Moreover, an increase of 30 IU/1 or more
from baseline was recorded in only 3.8% of patients
treated with meloxicam compared with 22.6% in the
piroxicam group (P = 0.0001) (Table II).
There were no significant differences between the
treatment groups with respect to the incidence of
adverse events, with 16.7% of patients treated with
STUDIES ON MELOXICAM (MOBIQ
54
TABLE UI
Frequency and percentage of adverse events according to WHO
system organ class a w « v < by the clinician to be possibly, probably
or definitely related to study medication
System organ class preferred term
Skin and appendage disorders
Central and peripheral nervous
system disorders
Hearing and vestibular disorders
GI system disorders
Heart rate and rhythm disorders
White cell and res. disorders
Platelet bleeding and clotting
disorders
Urinary system disorders
Body as a whole general disorders
Application site disorders
Meloxicam
(n = 144)
Piroxicam
(/i = 66)
5 (3.5)
5 (3.5)
0 (0)
1 (1.5)
1 (0.7)
9 (6.2)
0(0)
1 (0.7)
0(0)
0 (0)
0 (0)
1 (1.5)
0 (0)
1(1.5)
1 (0.7)
3 (2.1)
1 (0.7)
0 (0)
2 (3.0)
0 (0)
meloxicam and 12.1% treated with piroxicam
experiencing at least one adverse event (Table III). No
serious adverse events were reported in either group.
The overall safety profile was similar to that previously
observed with this class of drug and consisted mainly of
GI events (gastric pain, nausea and diarrhoea), skin
reactions (pruritus and rash), and central or peripheral
nervous system side-effects (headache and vertigo).
Laboratory analyses and cardiovascular parameters
showed no clinically significant changes from baseline
in either group.
Efficacy. Assessment of global efficacy by the patients
revealed a significant advantage for meloxicam over
piroxicam among those with RA (P - 0.007), and a
trend towards improvement with meloxicam among
those with OA. In patients with RA, global efficacy was
rated as 'very good' or 'rather good' by 62/68 (91.2%) of
those treated with meloxicam and only 20/27 (71.4%)
treated with piroxicam (P = 0.045). The corresponding
ratings in patients with OA were achieved by 66/76
(86.6%) of those treated with meloxicam and 32/39
(82.1%) treated with piroxicam. A large number of OA
patients rated meloxicam as 'very good' (40.8% of
meloxicam-treated patients vs 23.1% of piroxicamtreated patients).
Similarly good results were observed for the
clinician's assessment of global efficacy, with a
significant benefit for meloxicam over piroxicam among
patients with RA (P = 0.02) and OA (P = 0.02). Among
patients with RA, global efficacy ratings were considered 'very good' or 'rather good' in 62/68 (91.2%)
treated with meloxicam and 20/27 (74.1%) treated with
piroxicam (P = 0.045). In the OA group, 67/76 (88.2%)
patients treated with meloxicam and 32/39 (82.0%)
treated with piroxicam experienced 'very good' or
'rather good' global efficacy (Table IV).
The overall pain intensity experienced with RA and
OA at baseline was significantly reduced after the
final injection of both meloxicam and piroxicam
(P = 0.0001). Among patients with OA, the decrease in
pain intensity was significantly greater in the meloxicam
group (-34.8%) than in the group treated with
piroxicam (-22.1%) (P = 0.02). A similar trend was
TABLE IV
Global efficacy as assessed by the clinician at the final visit
OA
Meloxicam
Piroxicam
RA
Meloxicam
Piroxicam
Very
good
Rather
good
Rather
bad
Very
bad
36
31
(47.4%) (40.8%)
8
24
(20.5%) (61.5%)
8
(10.5%)
6
(15.4%)
1
(1.3%)
1
(2.6%)
25
37
(36.8%) (54.4%)
13
7
(48.2%) (25.9%)
6
(8.8%)
7
(25.9%)
Total
76
39
0
68
0
27
observed among patients with RA, although this did
not achieve statistical significance (-32.1% vs -23.3%).
Concomitant paracetamol treatment was limited in
both treatment groups but was greater among patients
with RA than among those with OA. The mean daily
dose was constantly <600 mg in patients with RA and
300 mg for those with OA. There were no significant
differences between the treatment groups with respect to
paracetamol consumption. Among patients with RA,
52.2% on meloxicam and 48.1% on piroxicam took
paracetamol at least once during the study; the
corresponding figures for patients with OA were 24.0%
and 31.6% respectively.
DISCUSSION
NSAIDs are the most commonly prescribed therapy
for rheumatoid disorders, and although chronic
treatment can be given orally, acute pain may
necessitate a rapid onset of effect which can best be
achieved with i.v. or i.m. administration. The current
study was undertaken to compare the local and overall
tolerability of an i.m. formulation of meloxicam with
i.m. piroxicam, an established treatment for rheumatic
conditions which shows good local tolerability [10].
Local tolerability was good in both treatment groups,
however, meloxicam was significantly better than
piroxicam for a number of parameters, including
presence of redness after the first injection and global
local tolerability after the first and final injections.
Any changes in serum CPK levels are an important
factor in the evaluation of local tolerability since CPK
is an indicator of muscle fibre damage [11, 12]. It is well
recognized that i.m. injections can result in elevated
CPK [13], which in turn may be due to a number of
factors including direct muscle trauma, chemotoxicity
or stimulation of histamine release [14]. Previous
studies with NSAIDs injected i.m. have reported mean
increases from baseline of 922% with diclofenac and
147% with piroxicam [13]. These changes tend to occur
~6-12 h after injection and may persist for 3 or 4 days
[14]. In the present study, there was no mean increase in
serum CPK levels in the meloxicam group, while
piroxicam was associated with a 59% increase; this
difference was statistically significant and emphasizes
the good local tolerability profile of meloxicam.
GHOZLAN ETAL.: TOLERABILITY OF INTRAMUSCULAR MELOXICAM
The overall safety of both drugs was good. Assessments of 'very good' were achieved by 84.0% of patients
treated with meloxicam and 83.3% treated with
piroxicam following evaluation by the clinician; the
corresponding percentages following assessment by the
patient were 81.2% and 80.3% respectively. The
incidence of systemic adverse events was similar in both
treatment groups and there were no serious events or
clinically relevant changes in laboratory parameters.
Assessments of efficacy, which were performed
separately for OA and RA, revealed that the global
efficacy of meloxicam was significantly better than that
of piroxicam in patients with RA and that overall pain
intensity was improved to a significantly greater extent
with meloxicam than with piroxicam in patients with
OA.
The results of this study are in accordance with
animal studies of local tolerability of i.v., i.m., dermal
and ocular formulations of meloxicam, all of which
showed excellent local and systemic tolerability [15].
When the tolerability of i.m. meloxicam was compared
with diclofenac and piroxicam in rabbits, diclofenac
caused considerably more tissue reddening than either
of the other two drugs. Both diclofenac and piroxicam,
but not meloxicam, resulted in the development of
necrotic areas in the muscle of the animals [15].
In conclusion, the local and overall tolerability of
i.m. meloxicam in patients with RA and OA was good.
Assessment of local tolerability showed an advantage in
favour of meloxicam over piroxicam which attained
statistical significance for a number of parameters, a
finding that was confirmed by muscular tolerability as
determined by changes in CPK. In addition, the efficacy
of meloxicam was superior to that of piroxicam. Thus,
meloxicam is suitable for i.m. administration in the
management of acute rheumatic pain, showing an
advantage in local tolerability and somewhat better
efficacy than the well-established NSAID, piroxicam, in
RA.
ACKNOWLEDGEMENTS
We would like to thank the following investigators for
all their help and support Dr Couloumere (Antibes),
Dr Herr (Schiltigheim), Dr Lanchon (Lisieux); Dr
Lapraz (Nice), Dr Morlock (Carcassonne), Professor
Sany (Montpellier), Dr Tauveron (Tours), Professor
Combe (Nimes), Dr Valente (Marseille), Dr Rocque
(Reims), DT Franck (Bordeaux) in France; and Dr Rohe
(Bad Schdnborn); Dr Niksch (Vreden), Dr Wittenhorst
(Bad Zwischenhahn), Dr Bruckle (Bad Nenndorf), Dr
Honneth (Essen), Dr Maleitzke (Bad Buchau) in
Germany.
55
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