Ignite Creation Date:
2024-05-05 @ 12:07 PM
Last Modification Date:
2024-10-26 @ 9:20 AM
Study NCT ID:
NCT00244153
Status:
UNKNOWN
Last Update Posted:
2006-09-11
First Post:
2005-10-25
Brief Title:
Intraarticular Opioids Vs Glucocorticosteroids in Gonarthritis
Sponsor:
Charite University Berlin Germany
Organization:
Charite University Berlin Germany
Study Overview
Official Title:
Intraarticular Application of Opioids Versus Glucocorticosteroids Versus Placebo in Rheumatoid Arthritis
Status:
UNKNOWN
Status Verified Date:
2004-02
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Intraarticular application of opioids versus glucocorticosteroids versus placebo in knee arthritis
study goals assessment of effectiveness and tolerability of locally applied morphine dexamethasone or placebo in knee arthritis
study goals assessment of effectiveness and tolerability of locally applied morphine dexamethasone or placebo in knee arthritis
Detailed Description:
Study background
Patients with chronic inflammatory arthritis eg rheumatoid arthritis undifferentiated oligoarthritis monarthritis suffer from recurrent pain functional impairment and impaired capacity Consequences of such hard to treat diseases are occupational incapacity and early retirement The treatment options we have today such as nonsteroidal antirheumatic drugs NSAIDs such as diclofenac glucocorticosteroids eg dexamethasone and disease modifying antirheumatic drugs such as methotrexate partly are effective but also have serious side effects and complications eg gastric and duodenal ulcers nephrotoxicity degeneration of cartilage cushings syndrome
A new therapeutic approach without such complications is represented by the intraarticular ia application of low-concentrated systemically inactive dosages of an opioid eg morphine This treatment showed a significant reduction of pain in patients with chronic arthritis in controlled clinical trials without systemic or local side effects 1 2 This effect is based on an activation of peripheral opioid receptors which could be identified on peripheral nerve endings of sensoric neurons 3-5 The activation of these opioid receptors leads to a decrease of neuronal excitability and the transmission of noziceptive impulses as well as to a reduced release of proinflammatory neurotransmitters eg substance p 6 Several studies showed that locally applied opioids act analgetic that such analgetic effects mainly occur in inflamed tissue that the analgetic effects increase with the degree of inflammation and that peripherally acting opioids act analgetic 6-9 In human beings the analgetic effect of peripherally applied opioid agonists has almost only been shown in patients with acute post-surgical pain 4 10-15 In a first case report 16 we found indices for the analgetic effect of ia given morphine in patients with chronic arthritic pain In patients with osteoarthritis a double blind cross-over study it was shown that 1mg morphine leads to a long-lasting analgetic effect up to 9 days 1 In a second controlled trial we compared patients with chronic joint inflammation in different diseases in regards of the analgetic effect of ia morphine 3 mg versus placebo versus a standard therapy with ia dexamethasone 4 mg 2 Dexamethasone as well as morphine lead to a significant pain reduction under rest and under strain compared to placebo This analgetic effect lasted up to 6 days after injection Moreover we found first indications for an anti-inflammatory effect as the number of inflammatory cells in the synovial fluid was reduced after the ia morphine application 2
In addition to the question whether morphine can stimulate local peripheral opioid receptors it should be investigated whether intraarticular morphine has an anti-inflammatory local effect in arthritis of the knee in the setting of inflammatory rheumatic diseases such as rheumatoid arthritis spondyloarthropathies undifferentiated oligoarthritis or monarthritis 17 19 31 This question should be answered through investigation of cellular infiltration and cytokine expression in the synovial membrane and synovial fluid
Next to the exogenous application of opioids also endogenous opioid peptides play an important role in inflammatory processes Experimental and clinical investigations show an expression of opioid peptides in immune cells which invade into inflamed tissue 3 4 6 20 21 Under certain circumstances these opioid peptides are locally released and unfold a strong analgetic effect through the activation of opioid receptors on peripheral sensoric nerve endings 22-24 Corticotropin-releasing factor CRF can release - similar as in the hypophysis- opioid peptides from immune cells 25-28 CRF receptors are located in regionally invaded immune cells and the number is up regulated among inflammatory cells 29 Experimental investigations from our or other groups showed a significant analgetic effect of local CRF which was given into the inflamed tissue 24 26 30
In this study we want to test the hypothesis that ia applied CRF leads to a reduction of pain intensity and pain duration in patients with inflammatory knee trauma Initially this effect is to be tested in acute and then - if successful- in chronic knee pain
Background for dosage
The intraarticular application of morphine 3mg and dexamethasone 4 mg respectively has turned out from previous studies 2 15 in patients with inflammatory knee joints of different causes without evidence of relevant systemic side effects
Background for patient selection
Several patients with inflammatory rheumatic diseases such as rheumatoid arthritis spondyloarthropathies undifferentiated oligoarthritis or monarthritis suffer from symptomatic knee arthritis despite intake of disease modifying drugs DMARDs or systemic low dose glucocorticosteroids To achieve a adequate comparability of the different drugs a patient number of 20 for each group seems to be sufficient Patients are supposed to have arthritis of the knee and a sufficient pain intensity according to the visual analogue scale for pain 30 mm Patients will be seen in the rheumatology department of the Klinikum Benjamin-Franklin Berlin Germany as well as in the Immanuel-Krankenhaus Berlin Germany examined Arthroscopies will only take place in the rheumatology department of the Klinikum Benjamin-Franklin Berlin Germany
References
1 Likar R Schäfer M Paulak F et al Intraarticular morphine analgesia in chronic pain patients with osteoarthritis Anesth Analg 1997841313-7
2 Stein A Yassouridis A Szopko C Helmke K Stein C Intraarticular morphine versus dexamethasone in chronic arthritis Pain 199983525-32
3 Stein C The control of pain in peripheral tissue by opioids N Engl J Med 19953321685-90
4 Stein C Pflüger M Yassouridis A et al No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia J Clin Invest 199698793-9
5 Mousa SA Zhang Q Sitte N Ji R Stein C beta-Endorphin-containing memory-cells and mu-opioid receptors undergo transport to peripheral inflamed tissue J Neuroimmunol 200111571-8
6 Stein C Machelska H Schäfer M Peripheral analgesic and antiinflammatory effects of opioids Z Rheumatol 200160416-24
7 Binder W Walker JS Effect of the peripherally selective kappa-opioid agonist asimadoline on adjuvant arthritis Br J Pharmacol 1998124647-54
8 Wilson JL Walker JS Antoon JS Perry MA Intercellular adhesion molecule-1 expression in adjuvant arthritis in rats inhibition by kappa-opioid agonist but not by NSAID J Rheumatol 199825499-505
9 Binder W Machelska H Mousa S et al Analgesic and antiinflammatory effects of two novel kappa opioid peptides Anesthesiology 2001941034-44
10 Stein C Comisel K Haimerl E et al Analgesic effect of intraarticular morphine after arthroscopic knee surgery N Engl J Med 19913251123-6
11 Khoury GF Chen ACN Garland DE Stein C Intraarticular morphine bupivacaine and morphinebupivacaine for pain control after knee videoarthroscopy Anesthesiology 199277263-6
12 Likar R Kapral S Steinkellner H Stein C Schäfer M Dose-dependency of intra-articular morphine analgesia Br J Anaesth 199983241-4
13 Schäfer M Peripheral opioid analgesia from experimental to clinical studies Curr Opin Anaesth 199912603-7
14 Gupta A Bodin L Holmstrom B Berggren L A systematic review of the peripheral analgesic effects of intraarticular morphine Anesth Analg 200193761-70
15 Kalso E Smith L McQuay HJ Moore A No pain no gain clinical excellence and scientific rigour - lessons learned from IA morphine Pain 200298 269-275
16 Khoury GF Garland DE Stein C Intraarticular opioid-local anesthetic combinations for chronic joint pain Middle East J Anesth 199412579-85
17 Simon AK Seipelt E Sieper J Divergent T-cell cytokine patterns in inflammatory arthritis Proc Natl Acad Sci U S A 1994918562-6
18 Yin Z Siegert S Neure L et al The elevated ratio of interferon gamma-interleukin-4-positive T cells found in synovial fluid and synovial membrane of rheumatoid arthritis patients can be changed by interleukin-4 but not by interleukin-10 or transforming growth factor beta Rheumatology Oxford 1999381058-67
19 Rudwaleit M Yin Z Siegert S et al Response to methotrexate in early rheumatoid arthritis is associated with a decrease of T cell derived tumour necrosis factor alpha increase of interleukin 10 and predicted by the initial concentration of interleukin 4 Ann Rheum Dis 200059311-4
20 Machelska H Cabot PJ Mousa SA Zhang Q Stein C Pain control in inflammation governed by selectins Nature Med 199841425-8
21 Rittner HL Brack A Machelska H et al Opioid peptide-expressing leukocytes identification recruitment and simultaneously increasing inhibition of inflammatory pain Anesthesiology 200195500-8
22 Stein C Hassan AHS Przewlocki R Gramsch C Peter K Herz A Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation Proc Natl Acad Sci USA 1990875935-9
23 Stein C Hassan AHS Lehrberger K Giefing J Yassouridis A Local analgesic effect of endogenous opioid peptides Lancet 1993342321-4
24 Schäfer M Carter L Stein C Interleukin-1 and corticotropin-releasing-factor inhibit pain by releasing opioids from immune cells in inflamed tissue Proc Natl Acad Sci USA 1994914219-23
25 Schäfer M Mousa SA Zhang Q Carter L Stein C Expression of corticotropin-releasing factor in inflamed tissue is required for intrinsic peripheral opioid analgesia Proc Natl Acad Sci USA 1996936096-100
26 Lariviere WR Melzack R The role of corticotropin-releasing factor in pain and analgesia Pain 2000841-12
27 Cabot PJ Carter L Gaiddon C et al Immune cell-derived -endorphin production release and control of inflammatory pain in rats J Clin Invest 1997100142-8
28 Cabot PJ Carter L Schäfer M Stein C Methionine-enkephalin- and Dynorphin A-release from immune cells and control of inflammatory pain Pain 200193207-12
29 Mousa SA Schäfer M Mitchell WM Hassan AHS Stein C Local upregulation of corticotropin- releasing hormone and interleukin-1 receptors in rats with painful hindlimb inflammation Eur J Pharmacol 1996311221-31
30 Schäfer M Mousa SA Stein C Corticotropin-releasing factor in antinociception and inflammation Eur J Pharmacol 19973231-10
31 Leirisalo-Repo M Prognosis course of disease and treatment of the spondyloarthropathies Rheum Dis Clin North Am 1998 Nov244737-51
Patients with chronic inflammatory arthritis eg rheumatoid arthritis undifferentiated oligoarthritis monarthritis suffer from recurrent pain functional impairment and impaired capacity Consequences of such hard to treat diseases are occupational incapacity and early retirement The treatment options we have today such as nonsteroidal antirheumatic drugs NSAIDs such as diclofenac glucocorticosteroids eg dexamethasone and disease modifying antirheumatic drugs such as methotrexate partly are effective but also have serious side effects and complications eg gastric and duodenal ulcers nephrotoxicity degeneration of cartilage cushings syndrome
A new therapeutic approach without such complications is represented by the intraarticular ia application of low-concentrated systemically inactive dosages of an opioid eg morphine This treatment showed a significant reduction of pain in patients with chronic arthritis in controlled clinical trials without systemic or local side effects 1 2 This effect is based on an activation of peripheral opioid receptors which could be identified on peripheral nerve endings of sensoric neurons 3-5 The activation of these opioid receptors leads to a decrease of neuronal excitability and the transmission of noziceptive impulses as well as to a reduced release of proinflammatory neurotransmitters eg substance p 6 Several studies showed that locally applied opioids act analgetic that such analgetic effects mainly occur in inflamed tissue that the analgetic effects increase with the degree of inflammation and that peripherally acting opioids act analgetic 6-9 In human beings the analgetic effect of peripherally applied opioid agonists has almost only been shown in patients with acute post-surgical pain 4 10-15 In a first case report 16 we found indices for the analgetic effect of ia given morphine in patients with chronic arthritic pain In patients with osteoarthritis a double blind cross-over study it was shown that 1mg morphine leads to a long-lasting analgetic effect up to 9 days 1 In a second controlled trial we compared patients with chronic joint inflammation in different diseases in regards of the analgetic effect of ia morphine 3 mg versus placebo versus a standard therapy with ia dexamethasone 4 mg 2 Dexamethasone as well as morphine lead to a significant pain reduction under rest and under strain compared to placebo This analgetic effect lasted up to 6 days after injection Moreover we found first indications for an anti-inflammatory effect as the number of inflammatory cells in the synovial fluid was reduced after the ia morphine application 2
In addition to the question whether morphine can stimulate local peripheral opioid receptors it should be investigated whether intraarticular morphine has an anti-inflammatory local effect in arthritis of the knee in the setting of inflammatory rheumatic diseases such as rheumatoid arthritis spondyloarthropathies undifferentiated oligoarthritis or monarthritis 17 19 31 This question should be answered through investigation of cellular infiltration and cytokine expression in the synovial membrane and synovial fluid
Next to the exogenous application of opioids also endogenous opioid peptides play an important role in inflammatory processes Experimental and clinical investigations show an expression of opioid peptides in immune cells which invade into inflamed tissue 3 4 6 20 21 Under certain circumstances these opioid peptides are locally released and unfold a strong analgetic effect through the activation of opioid receptors on peripheral sensoric nerve endings 22-24 Corticotropin-releasing factor CRF can release - similar as in the hypophysis- opioid peptides from immune cells 25-28 CRF receptors are located in regionally invaded immune cells and the number is up regulated among inflammatory cells 29 Experimental investigations from our or other groups showed a significant analgetic effect of local CRF which was given into the inflamed tissue 24 26 30
In this study we want to test the hypothesis that ia applied CRF leads to a reduction of pain intensity and pain duration in patients with inflammatory knee trauma Initially this effect is to be tested in acute and then - if successful- in chronic knee pain
Background for dosage
The intraarticular application of morphine 3mg and dexamethasone 4 mg respectively has turned out from previous studies 2 15 in patients with inflammatory knee joints of different causes without evidence of relevant systemic side effects
Background for patient selection
Several patients with inflammatory rheumatic diseases such as rheumatoid arthritis spondyloarthropathies undifferentiated oligoarthritis or monarthritis suffer from symptomatic knee arthritis despite intake of disease modifying drugs DMARDs or systemic low dose glucocorticosteroids To achieve a adequate comparability of the different drugs a patient number of 20 for each group seems to be sufficient Patients are supposed to have arthritis of the knee and a sufficient pain intensity according to the visual analogue scale for pain 30 mm Patients will be seen in the rheumatology department of the Klinikum Benjamin-Franklin Berlin Germany as well as in the Immanuel-Krankenhaus Berlin Germany examined Arthroscopies will only take place in the rheumatology department of the Klinikum Benjamin-Franklin Berlin Germany
References
1 Likar R Schäfer M Paulak F et al Intraarticular morphine analgesia in chronic pain patients with osteoarthritis Anesth Analg 1997841313-7
2 Stein A Yassouridis A Szopko C Helmke K Stein C Intraarticular morphine versus dexamethasone in chronic arthritis Pain 199983525-32
3 Stein C The control of pain in peripheral tissue by opioids N Engl J Med 19953321685-90
4 Stein C Pflüger M Yassouridis A et al No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia J Clin Invest 199698793-9
5 Mousa SA Zhang Q Sitte N Ji R Stein C beta-Endorphin-containing memory-cells and mu-opioid receptors undergo transport to peripheral inflamed tissue J Neuroimmunol 200111571-8
6 Stein C Machelska H Schäfer M Peripheral analgesic and antiinflammatory effects of opioids Z Rheumatol 200160416-24
7 Binder W Walker JS Effect of the peripherally selective kappa-opioid agonist asimadoline on adjuvant arthritis Br J Pharmacol 1998124647-54
8 Wilson JL Walker JS Antoon JS Perry MA Intercellular adhesion molecule-1 expression in adjuvant arthritis in rats inhibition by kappa-opioid agonist but not by NSAID J Rheumatol 199825499-505
9 Binder W Machelska H Mousa S et al Analgesic and antiinflammatory effects of two novel kappa opioid peptides Anesthesiology 2001941034-44
10 Stein C Comisel K Haimerl E et al Analgesic effect of intraarticular morphine after arthroscopic knee surgery N Engl J Med 19913251123-6
11 Khoury GF Chen ACN Garland DE Stein C Intraarticular morphine bupivacaine and morphinebupivacaine for pain control after knee videoarthroscopy Anesthesiology 199277263-6
12 Likar R Kapral S Steinkellner H Stein C Schäfer M Dose-dependency of intra-articular morphine analgesia Br J Anaesth 199983241-4
13 Schäfer M Peripheral opioid analgesia from experimental to clinical studies Curr Opin Anaesth 199912603-7
14 Gupta A Bodin L Holmstrom B Berggren L A systematic review of the peripheral analgesic effects of intraarticular morphine Anesth Analg 200193761-70
15 Kalso E Smith L McQuay HJ Moore A No pain no gain clinical excellence and scientific rigour - lessons learned from IA morphine Pain 200298 269-275
16 Khoury GF Garland DE Stein C Intraarticular opioid-local anesthetic combinations for chronic joint pain Middle East J Anesth 199412579-85
17 Simon AK Seipelt E Sieper J Divergent T-cell cytokine patterns in inflammatory arthritis Proc Natl Acad Sci U S A 1994918562-6
18 Yin Z Siegert S Neure L et al The elevated ratio of interferon gamma-interleukin-4-positive T cells found in synovial fluid and synovial membrane of rheumatoid arthritis patients can be changed by interleukin-4 but not by interleukin-10 or transforming growth factor beta Rheumatology Oxford 1999381058-67
19 Rudwaleit M Yin Z Siegert S et al Response to methotrexate in early rheumatoid arthritis is associated with a decrease of T cell derived tumour necrosis factor alpha increase of interleukin 10 and predicted by the initial concentration of interleukin 4 Ann Rheum Dis 200059311-4
20 Machelska H Cabot PJ Mousa SA Zhang Q Stein C Pain control in inflammation governed by selectins Nature Med 199841425-8
21 Rittner HL Brack A Machelska H et al Opioid peptide-expressing leukocytes identification recruitment and simultaneously increasing inhibition of inflammatory pain Anesthesiology 200195500-8
22 Stein C Hassan AHS Przewlocki R Gramsch C Peter K Herz A Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation Proc Natl Acad Sci USA 1990875935-9
23 Stein C Hassan AHS Lehrberger K Giefing J Yassouridis A Local analgesic effect of endogenous opioid peptides Lancet 1993342321-4
24 Schäfer M Carter L Stein C Interleukin-1 and corticotropin-releasing-factor inhibit pain by releasing opioids from immune cells in inflamed tissue Proc Natl Acad Sci USA 1994914219-23
25 Schäfer M Mousa SA Zhang Q Carter L Stein C Expression of corticotropin-releasing factor in inflamed tissue is required for intrinsic peripheral opioid analgesia Proc Natl Acad Sci USA 1996936096-100
26 Lariviere WR Melzack R The role of corticotropin-releasing factor in pain and analgesia Pain 2000841-12
27 Cabot PJ Carter L Gaiddon C et al Immune cell-derived -endorphin production release and control of inflammatory pain in rats J Clin Invest 1997100142-8
28 Cabot PJ Carter L Schäfer M Stein C Methionine-enkephalin- and Dynorphin A-release from immune cells and control of inflammatory pain Pain 200193207-12
29 Mousa SA Schäfer M Mitchell WM Hassan AHS Stein C Local upregulation of corticotropin- releasing hormone and interleukin-1 receptors in rats with painful hindlimb inflammation Eur J Pharmacol 1996311221-31
30 Schäfer M Mousa SA Stein C Corticotropin-releasing factor in antinociception and inflammation Eur J Pharmacol 19973231-10
31 Leirisalo-Repo M Prognosis course of disease and treatment of the spondyloarthropathies Rheum Dis Clin North Am 1998 Nov244737-51
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None