Current Medical Research and Opinion (1996), 13, No. 7, 363-377
The efficacy and tolerability of an 8­day administration of intravenous and oral meloxicam: a comparison with intramuscular and oral diclofenac in patients with acute lumbago	Klaus Colberg, M.D.* Marceline Hettich, M.D.† Ralf Sigmund, M.D.† and Frank L. Degner, M.D.† for the German Meloxicam Ampoule Study Group‡ *D-23795 Bad Segeberg, Germany †Dr Karl Thomae GmbH, D-88397 Biberach, Germany Accepted: 11th April 1996

Summary

In this controlled, randomized, parallel and open multicentre study, the efficacy and tolerability of a regimen comprising intravenous (i.v.) meloxicam followed by oral therapy was compared with a standard regimen of intramuscular (i.m.) diclofenac followed by oral dosing in patients with acute lumbago. Of a total of 183 patients, 92 were randomized to receive meloxicam 15 mg i.v. on day 1 followed by 7 days oral treatment with one 15 mg tablet daily, and 91 patients received diclofenac 75 mg i.m. on day 1 followed by 7 days treatment with one 100 mg slow release tablet daily. Pain on movement and limitation of activities were assessed by patients and physicians using questionnaires. Meloxicam i.v. demonstrated a significantly faster median time of onset of analgesic action (30 minutes), compared with diclofenac i.m. (60 minutes). The reduction in pain during movement 30 minutes after injection was also significantly in favour of meloxicam. Assessments of global efficacy indicated that meloxicam was significantly better than diclofenac as rated by investigators (p = 0.02) and patients (p = 0.01). Moreover, the rating of investigators and patients for local and global tolerance was significantly in favour of meloxicam (p < 0.05) and improvements in the quality of life were almost significant (p = 0.053). Fewer adverse events, particularly of a gastrointestinal (GI) nature, occurred in the meloxicam group compared with the diclofenac group. This study therefore demonstrates that meloxicam 15 mg i.v. followed by oral therapy is both efficacious and well tolerated in the treatment of acute lumbago, and compares favourably with the standard NSAID, diclofenac, in this indication.

Key Words

Introduction

Millions of people each year suffer from lumbago, the general term for low back pain. It is estimated that, during 1988 and 1989, 52.6 million certified working days were lost due to sickness absence as a consequence of lumbago, constituting the largest single cause of total sick days in the U.K.¹⁴ Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely as analgesics for people with acute lumbago as they are the only non-opiate derivatives providing long-lasting analgesia, making them effective for overnight use.¹⁴

Meloxicam is a new enolic acid derived NSAID, shown to be safe and effective in the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA) in doses of 7.5 and 15 mg. More than 5000 patients with RA, OA, sciatica or low back pain have been successfully treated with meloxicam and the safety of meloxicam has been assessed over 1475 man-years of exposure, with more than 400 patients being treated for over a year.⁹

NSAIDs produce their anti-inflammatory activity by inhibition of the enzyme cyclooxygenase (COX), resulting in inhibition of prostaglandin biosynthesis.¹ Recently, two isoforms of COX have been identified. The constitutive form (COX-1) is present in cells under physiological conditions and is responsible for the cytoprotective and antithrombotic action of prostaglandins, whereas COX-2 is induced in fibroblasts, macrophages and some other cells by pro-inflammatory stimuli and cytokines.^32, 45 Meloxicam shows greater selectivity with regard to COX-2 inhibition than standard NSAIDs such as piroxicam and indomethacin.^10, 12, 46 Compounds demonstrating selectivity towards COX-2 should have fewer side effects and a less irritant action to the stomach.⁴⁴

A comparison of the ulcerogenic dose and the effective anti-inflammatory dose in animals revealed a superior therapeutic margin compared with other NSAIDs,^11, 13 as confirmed by the clinical database of meloxicam.⁹ In a global analysis of all meloxicam clinical studies, meloxicam was shown to be superior with respect to gastrointestinal (GI) tolerability compared with standard doses of piroxicam, diclofenac and naproxen.⁹ Meloxicam is almost completely absorbed from the GI tract following oral administration. The drug is widely distributed with no persistence in any particular tissue. The pharmacokinetic properties of meloxicam allow a single daily dose and a steady state is reached with oral dosage after 4 days.⁴² The plasma elimination half-life is about 20 hours⁴² in man, rat and dog. Meloxicam is bound to proteins by more than 99%⁴ and is metabolized in the liver to inactive metabolites which are excreted equally via the urine and faeces.⁵

The rationale for this study was the evaluation of efficacy (particularly with regard to the time to onset of action) and tolerance of meloxicam i.v. followed by oral therapy, in comparison with the standard i.m. and oral treatment with diclofenac, a reference therapy used commonly in this indication.

Patients and methods

In this controlled, randomized, parallel and open multicentre study, patients were recruited from 12 centres located in Germany. The study was reviewed and approved by the Ethics Committee of Freiburg and was conducted in accordance with the provisions of the Declaration of Helsinki 1974 (latest version). All patients gave informed consent to participate in the study.

Male and female patients aged 18 years or older were recruited. All patients suffered from acute lumbago due to muscular and skeletal tension or sprain to the lumbar spinal column and intermittent or constant pain between spinal column, 12th rib, posterior axillary line and gluteal fold. The lumbago attack had to have started within 48 hours prior to treatment.

Exclusion criteria constituted: patients recruited in other clinical trials 4 weeks before or during the study; patients with chronic or chronically recurrent lumbago, i.e. case history of more than two attacks of lumbago within the last six months; patients with clinical signs or symptoms of a disk prolapse; patients with whiplash injury of the spinal column or direct trauma to the spine; patients with clinical signs to suggest history of or active GI ulcer; patients with clinical signs or history of coagulation disorders or tendency to bleed; patients with known hypersensitivity to analgesics, antipyretics and NSAIDs; patients receiving oral anticoagulants or lithium therapy as well as patients with previous treatment or treatment of present lumbago attack with NSAIDs or analgesics other than acetylsalicylic acid or paracetamol, muscle relaxants, spasmolytics, anxiolytics or physiotherapy (stretching, massage, chiropraxis, microwave or infrared radiation, corset). Finally, pregnant or breast-feeding women and women without adequate contraception were also excluded from the study.

Meloxicam was supplied by Dr. Karl Thomae GmbH as 1.5 ml ampoules (meloxicam 15 mg) and 15 mg tablets. Diclofenac was delivered as 3 ml ampoules (diclofenac 75 mg) and 100 mg film-coated SR tablets. Meloxicam was injected intravenously and diclofenac intramuscularly on day 1. Patients were instructed to take 1 tablet meloxicam or 1 tablet diclofenac daily, from day 2 to 8.

Patient assessments were carried out on days 1, 2 and 8. The two primary endpoints for assessment of efficacy were the time until onset of analgesic action and global efficacy. The time until onset of analgesic action comprised the time following injection at which pain on movement began to subside (beginning of effect). Global efficacy was assessed by the investigator and the patient at the end of the study on a verbal rating scale (VRS) using the ratings 'very good', 'good', 'bad' and 'very bad'. There were two secondary endpoints: pain on movement of the lumbar region and limitation of everyday activities. Pain on movement was assessed both by the patient immediately after injection and by the physician during the study. Patient assessments involved filling in a VRS with the ratings 'no pain', 'mild pain', 'moderate pain', 'severe pain' and 'very severe pain', before and at 15, 30, 60 and 90 minutes after injection. Physicians questioned patients prior to treatment, on day 2 and on day 8, using the same VRS. For the limitation of everyday activities, the patient was questioned according to a VRS with the ratings 'no limitation', 'mild limitation', 'moderate limitation', 'severe limitation' and 'very severe limitation'. The answers were recorded immediately before the beginning of treatment, on the next day and at the final visit on day 8. At visit 1 and the final visit the patient was asked to complete a modified questionnaire of life quality³ referring to several aspects of daily life, including the questions: 'could you now pursue regular activities in your profession and at home', '...exert yourself physically', '...move your body freely and without pain', etc. The answers to the quality questions were classified into such categories as 'with ease', 'not at all', 'not applicable' or 'don't know'.

Global tolerance was assessed for safety by the investigator and the patient at the end of the study using a VRS with the ratings 'very good', 'good', 'moderate', 'bad' and 'very bad'. Local tolerance was assessed by investigator and patient at visit 2 using the same VRS. As additional safety parameters, haematology (haemoglobin, erythrocytes, leucocytes, platelets) and biochemistry (sodium, potassium, creatinine, bilirubin, SGPT and SGOT) were assessed at visit 1, before treatment and at the final visit on day 8.

The occurrence of adverse events (AEs), withdrawals due to poor tolerance and the time of such a withdrawal were recorded at each visit. Events were classified into mild, moderate and severe and classified as serious if one of the following events had occurred: death; immediate danger to life; continuous or severe damage; hospitalization or prolongation of hospitalization; congenital malformation; cancer; overdosage and other comparable medical criteria. The relation to the trial medication was indicated as 'yes' or 'no'. Compliance was assessed by the dispensing record and the number of trial medication capsules taken.

Statistics

Data were evaluated on an intent-to-treat basis. For confirmatory analysis of the primary endpoints, the generalized Wilcoxon-square test was used for time until onset of analgesic action and the chi-square test was used for global efficacy. The secondary endpoints were evaluated by explorative analyses using the two sample t-test, U-test or the chi-square test. AEs and laboratory data values were checked for clinically relevant changes. No replacement of missing values and no transformations were planned except for pain on movement 15-90 minutes after injection (in case of missing values, the last observed value was carried forward). Patients without values for the onset of action were assigned a censored time of 10 hours (life table methods). This was also applicable for patients with an onset of action longer than 10 hours.

Results

Twelve centres of orthopaedic surgeons, internal specialists and general practitioners participated in the study. There were no centre effects.

One hundred and eighty-three patients were enrolled and subsequently randomized, placing 92 patients into the meloxicam treatment group (51 males and 41 females) and 91 into the diclofenac treatment group (52 males and 39 females). Five patients in each group discontinued the trial; of these, three patients in each treatment group terminated because of insufficient efficacy and two patients in each treatment group because of an adverse event. Consequently, 87 patients in the meloxicam group and 86 patients in the diclofenac group completed the study.

The mean age ( S.D.) in the meloxicam group was 52.7 15.3 years, in the diclofenac group 48.2  14.8 years, resulting in a statistically significant difference between the treatment groups ( p = 0.043). However, this was believed to be of no clinical significance. The majority of patients (58 patients in the meloxicam group, 66 in the diclofenac group) had had no attacks of lumbago during the last six months. The mean time of onset of the current lumbago attack was 18.3 10.5 hours prior to treatment in the meloxicam group and 18.8 11.6 hours in the diclofenac group, revealing no difference between treatment groups. There was also no difference between treatment groups with regard to the number of lumbago attacks during the previous six months. In general both treatment groups were comparable concerning their baseline values.

Efficacy

For meloxicam 15 mg i.v. the median time of onset of analgesic action was 30 minutes, for diclofenac 75 mg i.m. 60 minutes. The quicker onset of action for meloxicam was statistically significant ( p = 0.048) (Figure 1).

Global efficacy, rated at the end of the trial by patient and investigator, was significantly in favour of meloxicam. In the meloxicam group, the majority of investigators (57%) judged global efficacy to be 'very good' and 35% to be 'good', whereas in the diclofenac group only 36% of investigators judged global efficacy to be 'very good' and the majority (53%) to be 'good'. The difference between the groups was statistically significant ( p = 0.02). The majority of patients in the meloxicam group (57%) regarded global efficacy to be 'very good' and 32% to be 'good', whereas only 37% of the patients in the diclofenac group judged global efficacy to be 'very good', the majority (54%) regarding the overall efficacy as only 'good'. The difference between the groups was statistically significant ( p = 0.01).

The fall in the percentage of patients with moderate to very severe pain on movement, 90 minutes after injection, is depicted in Figure 2. In patients receiving meloxicam, there was a 61% reduction in those with moderate to very severe pain from 15 to 90 minutes after injection, compared with 43% in the diclofenac group.

Figure 1.
Time until onset of action (proportion of patients not noticing an onset of action)^‡

Figure 2.
Reduction in percentage of patients experiencing moderate-very severe pain during movement, up to 90 minutes after injection

Most patients in both groups still reported severe pain 15 minutes after injection. However, 48% of patients in the meloxicam group were now exhibiting moderate or lower pain during movement, with no patients with very severe pain. Reduction of pain on movement was not as pronounced in the diclofenac group, only 39% exhibiting moderate or lower pain, 9% experiencing very severe pain, resulting in a significant difference between the groups in favour of meloxicam ( p = 0.005).

Thirty minutes after injection, only 23% of meloxicam patients still expressed severe pain, compared with 45% in the diclofenac group. There was a significant difference between the treatment groups ( p = 0.0001), demonstrating that meloxicam showed a significantly quicker onset of analgesic action at 30 minutes, in comparison with diclofenac.

After 60 minutes, 39% of the meloxicam treatment group reported moderate pain and 39% mild pain. Thirty-eight per cent of patients in the diclofenac group complained of moderate pain, with only 24% experiencing mild pain, resulting in a significant difference between the groups in favour of meloxicam ( p = 0.0042).

Finally, 90 minutes after injection, the majority of patients in the meloxicam group (55%) rated mild pain, whereas in the diclofenac group, only 36% experienced mild pain, 32% of patients still rating moderate pain, resulting in a significant difference between the groups in favour of meloxicam ( p = 0.0105).

In the meloxicam group, there were more patients with severe and very severe pain at baseline compared to diclofenac. Apart from the quicker onset of analgesic action within 15 to 90 minutes after injection in favour of meloxicam, the increased number of patients in the meloxicam group changing to mild and moderate pain after injection might have also influenced the highly significant differences between the groups after 15 to 90 minutes after injection.

During the remainder of the trial, the pain decrease was slightly in favour of meloxicam (Table I), but there were no significant differences between the groups.

At the start of the trial, the majority of cases in the meloxicam treatment group (63%) suffered a severe limitation of daily activities, dropping to 40% experiencing moderate limitation and 36% with mild limitation on day 2. By trial end, 67% of patients in the meloxicam treatment group were experiencing no limitation in daily activities. Fifty-five per cent of patients in the diclofenac treatment group also reported severe limitation at trial start, dropping to 51% experiencing moderate and 29% mild limitation on day 2. By trial end, only 54% were experiencing no limitation and 38% still suffered mild limitation of daily activities. There were no significant differences between the groups at any visits. However, the sum score of daily activities at trial end according to the life quality questionnaire rated meloxicam to be almost significantly better compared with diclofenac ( p = 0.053).

*The percentage in total refers to 100%. However, in total 1 patient is missing in each group at trial end: Meloxicam 91 patients + 1 missing value = 100%; Diclofenac 90 patients + 1 missing value = 100%.

†Cumulative percentages are not equal to 100% due to rounding errors and missing values.

Safety

In assessments of local tolerance (Table II), a vast majority of investigators (86%) and patients (80%) considered local tolerance in the meloxicam group to be 'very good'. However, only 59% of investigators and 55% of patients rated diclofenac 'very good'. These results were highly significant in favour of meloxicam for both investigators ( p < 0.001) and patients ( p = 0.001).

*The percentage in total refers to 100%. However, in total 1 patient is missing in each group at trial end: Meloxicam 91 patients + 1 missing value = 100%; Diclofenac 90 patients + 1 missing value = 100%.

†Cumulative percentages are not equal to 100% due to rounding errors and missing value(s).

The global tolerance rating by investigators and patients was also clearly in favour of meloxicam (Table III). Seventy-seven per cent of investigators rated the global tolerance to meloxicam as 'very good', only 60% rating global tolerance to diclofenac as 'very good' (  p = 0.042). Patients' assessments were comparable with investigators' ( p = 0.016).

*The percentage in total refers to 100%. However, in total 1 patient is missing from the diclofenac group by trial end and 2 patients are missing from the meloxicam group at trial end: Meloxicam 92 patients + 2 missing values = 100%. Diclofenac 91 patients + 1 missing value = 100%.

†Cumulative percentages are not equal to 100% due to rounding errors and missing value(s).

Adverse events

Six patients in the meloxicam group and eight patients in the diclofenac group experienced a total of 17 AEs (Table IV). Of these, only one event was classed as severe in each group. In the meloxicam group, five events were classified as mild,

only two being moderate, whereas in the diclofenac group, there were four moderate events and four mild events experienced. Six GI adverse events occurred in the diclofenac group compared with three in the meloxicam group, the most frequent AE in the diclofenac group being of a GI nature, i.e. dyspepsia. General, central and peripheral nervous disorders occurred rarely and could not be definitely attributed to meloxicam.

The one severe AE occurring in each group was classified as not related to treatment. The event in the meloxicam group was not serious (aggravation of initial condition), however, it led to discontinuation of the drug. The patient in the diclofenac group experienced a rupture of the Achilles tendon, classified as serious and leading to discontinuation.

None of the observed AEs led to changes in dosage and there were no abnormal trends during laboratory assessments in the meloxicam group.

Discussion

The significantly favourable efficacy of meloxicam over diclofenac in the treatment of acute pain is demonstrated by the present study, as the i.v. injection of meloxicam 15 mg exhibited a significantly quicker onset of analgesic action (30 minutes) compared with the i.m. injection of diclofenac (60 minutes). Pain on movement also improved significantly in favour of meloxicam, 15-90 minutes after injection.

The rating of global efficacy by investigators and patients at trial end was significantly in favour of meloxicam. During oral therapy, meloxicam showed the same activity of effective pain reduction and improvement of daily activities as diclofenac for each time point, whereas the sum score of life quality at trial end referring to several aspects of daily life, e.g. moving the body freely without pain, performing a regular activity at work/home, etc., was almost significant in favour of meloxicam.

Both parenteral and oral treatment with meloxicam over the 8 days was well tolerated. The rating of global and local tolerance by investigators and patients at trial end was significantly in favour of meloxicam. It is also worth noting that patients in the meloxicam group were slightly older compared with patients in the diclofenac group.

Normally, NSAIDs are effective drugs when prescribed at the recommended dosage. However, all of them are associated with a considerable incidence of adverse effects, some, particularly upper GI effects, being potentially life-threatening.^{15, 16, 21, 28, 43}

The spectrum of selective activities of standard NSAIDs against the two cyclooxygenase enzymes (COX-1 and COX-2) ranges from a selectivity for inhibiting COX-1 to equal potency for both (e.g. diclofenac).^32, 44 This variable selectivity in inhibiting the two different isoforms and the resultant ranking by COX-1: COX-2 ratio may explain the difference in adverse event ratings, particularly GI event ratings, of standard NSAIDs such as diclofenac, indomethacin, piroxicam, naproxen and ibuprofen at their anti-inflammatory doses.^{6, 17, 19, 27, 28, 32, 35, 45}

Meloxicam has been widely evaluated in OA^{20, 22-24, 30, 31} and RA^25, 26, 34 and is also used in the treatment of patients with acute lumbago in parenteral and oral applications, alongside standard NSAIDs^8, 36, 38 such as diclofenac,^7, 39 piroxicam,^37, 47 indomethacin²⁹ and tenoxicam.⁴¹

Good results using meloxicam ampoules with regard to tolerance and pharmacokinetics encourage the use of meloxicam in acute lumbago.^33, 40, 42 Quick onset of analgesic action is a quality particularly important in this painful condition, as acute pain necessitates a rapid onset of analgesic effect. Comparative studies with meloxicam ampoule and capsule formulations revealed time to maximum improvement of induced pain to be significantly shorter with i.m. injections of meloxicam than with oral capsules,² further comparative studies with i.m. meloxicam and piroxicam in patients with RA revealed meloxicam to be superior to piroxicam, a standard NSAID used in the treatment of this indication.¹⁸ Local tolerability of i.m. meloxicam is significantly better than i.m. piroxicam in the treatment of both RA and OA¹⁸ and local tolerability of i.m. meloxicam in patients with sciatica is excellent.²

Meloxicam has been shown to be better tolerated than other NSAIDs regarding safety; GI safety in particular is superior to that of other NSAIDs.⁹ Regarding the potentially most serious GI AEs, i.e. perforation, ulceration and bleeding, meloxicam has shown on average a 6- to 9-fold (7.5 mg) and a 2- to 3-fold (15 mg) risk reduction compared with diclofenac 100 mg slow release and piroxicam 20 mg respectively.⁹ Results from the present study are in line with the previous findings of improved GI safety with meloxicam treatment, as there were fewer GI adverse events in the oral and i.v. meloxicam treatment group than in the oral and i.m. diclofenac treatment group. Laboratory and safety profiles were also generally consistent with previous experience of meloxicam.

In conclusion, both i.v. and oral formulations of meloxicam show a clear advantage in efficacy and tolerability over i.m. and oral diclofenac in the treatment of patients with acute lumbago. The better tolerability of meloxicam was demonstrated by significantly better local and global tolerability compared with diclofenac. Thus, meloxicam is eminently suitable for both i.v. and oral administration in the treatment of this indication.

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Meloxicam Ampoule Study Group Authors:

Dr. med. Klaus Colberg, Kurhausstr. 14, D-23795 Bad Segeberg
Dr. med. Marceline Hettich, Dr. Karl Thomae GmbH, D-88397 Biberach
Dr. med. Frank Degner, Dr. Karl Thomae GmbH, D-88397 Biberach
Dr. med. Ralf Sigmund, Dr. Karl Thomae GmbH, D-88397 Biberach

Participating Physicians:

Dr. med. Thomas Anke, Beethovenstr. 14, D-53773 Hennef/Sieg
Dr. med. Richard Barabasch, Friedenstr. 26, D-76461 Muggenstorm
Dr. med. Michael Benning, Holland 23, D-32052 Herford
Dr. med. Doggaz, Em Koddes 9, D-52531 Übach-Palenberg
Dr. med. Ekkehart Hülsemann, Wilhelmstr. 6, D-35683 Dillenburg
Dr. med. Günter Kern, Gemeinschaftspraxis,
Dr. med. H. D. Reder, Alleestr. 34, D­96114 Hirschaid
Dr. med. GE von Manteuffel, Huteweg 9, D-35041 Marburg-Wehrda
Dr. med. Jochen Pique, Nordstr. 6, D-28857 Syke
Dr. med. F. Radermacher, Kirchhellenerstr. 6, D-45966 Gladbeck
Dr. med. Hermann Seifert, Am Schl`ssle 4a, D-87600 Kaufbeuren-Oberbeuren
Dr. med. Helmut Zimmer, Klinikweg 16, D-85643 Steinh`ring