Rheumatic Disease Clinical Trial
Official title:
Intraarticular Application of Opioids Versus Glucocorticosteroids Versus Placebo in Rheumatoid Arthritis
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 background
Patients with chronic inflammatory arthritis (e.g. 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 (e.g. dexamethasone) and disease modifying
antirheumatic drugs (such as methotrexate) partly are effective but also have serious side
effects and complications (e.g. gastric and duodenal ulcers, nephrotoxicity, degeneration of
cartilage, cushing´s syndrome…).
A new therapeutic approach without such complications is represented by the intraarticular
(i.a.) application of low-concentrated, systemically inactive dosages of an opioid (e.g.
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 (e.g.
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 i.a. 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 i.a. morphine (3 mg) versus placebo versus a standard
therapy with i.a. 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 i.a. 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 i.a. 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 1997;84:1313-7.
2. Stein A, Yassouridis A, Szopko C, Helmke K, Stein C. Intraarticular morphine versus
dexamethasone in chronic arthritis. Pain 1999;83:525-32.
3. Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med
1995;332:1685-90.
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 1996;98:793-9.
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
2001;115:71-8.
6. Stein C, Machelska H, Schäfer M. Peripheral analgesic and antiinflammatory effects of
opioids. Z Rheumatol 2001;60:416-24.
7. Binder W, Walker JS. Effect of the peripherally selective kappa-opioid agonist,
asimadoline, on adjuvant arthritis. Br J Pharmacol 1998;124:647-54.
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 1998;25:499-505.
9. Binder W, Machelska H, Mousa S, et al. Analgesic and antiinflammatory effects of two
novel kappa opioid peptides. Anesthesiology 2001;94:1034-44.
10. Stein C, Comisel K, Haimerl E, et al. Analgesic effect of intraarticular morphine after
arthroscopic knee surgery. N Engl J Med 1991;325:1123-6.
11. Khoury GF, Chen ACN, Garland DE, Stein C. Intraarticular morphine, bupivacaine and
morphine/bupivacaine for pain control after knee videoarthroscopy. Anesthesiology
1992;77:263-6.
12. Likar R, Kapral S, Steinkellner H, Stein C, Schäfer M. Dose-dependency of
intra-articular morphine analgesia. Br J Anaesth 1999;83:241-4.
13. Schäfer M. Peripheral opioid analgesia: from experimental to clinical studies. Curr
Opin Anaesth 1999;12:603-7.
14. Gupta A, Bodin L, Holmstrom B, Berggren L. A systematic review of the peripheral
analgesic effects of intraarticular morphine. Anesth Analg 2001;93:761-70.
15. Kalso E, Smith L, McQuay HJ, Moore A. No pain, no gain: clinical excellence and
scientific rigour - lessons learned from IA morphine. Pain 2002;98: 269-275.
16. Khoury GF, Garland DE, Stein C. Intraarticular opioid-local anesthetic combinations for
chronic joint pain. Middle East J Anesth 1994;12:579-85.
17. Simon AK, Seipelt E, Sieper J. Divergent T-cell cytokine patterns in inflammatory
arthritis. Proc Natl Acad Sci U S A 1994;91:8562-6.
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) 1999;38:1058-67.
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 2000;59:311-4.
20. Machelska H, Cabot PJ, Mousa SA, Zhang Q, Stein C. Pain control in inflammation
governed by selectins. Nature Med 1998;4:1425-8.
21. Rittner HL, Brack A, Machelska H, et al. Opioid peptide-expressing leukocytes:
identification, recruitment, and simultaneously increasing inhibition of inflammatory
pain. Anesthesiology 2001;95:500-8.
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 1990;87:5935-9.
23. Stein C, Hassan AHS, Lehrberger K, Giefing J, Yassouridis A. Local analgesic effect of
endogenous opioid peptides. Lancet 1993;342:321-4.
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
1994;91:4219-23.
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 1996;93:6096-100.
26. Lariviere WR, Melzack R. The role of corticotropin-releasing factor in pain and
analgesia. Pain 2000;84:1-12.
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 1997;100:142-8.
28. Cabot PJ, Carter L, Schäfer M, Stein C. Methionine-enkephalin- and Dynorphin A-release
from immune cells and control of inflammatory pain. Pain 2001;93:207-12.
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 1996;311:221-31.
30. Schäfer M, Mousa SA, Stein C. Corticotropin-releasing factor in antinociception and
inflammation. Eur J Pharmacol 1997;323:1-10.
31. Leirisalo-Repo M. Prognosis, course of disease, and treatment of the
spondyloarthropathies. Rheum Dis Clin North Am. 1998 Nov;24(4):737-51
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment
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