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Intraarticular morphine versus dexamethasone in chronic arthritis
Pain 83 (1999) 525±532 www.elsevier.nl/locate/pain
Intraarticular morphine versus dexamethasone in chronic arthritis Andreas Stein a, Alexander Yassouridis b, Christopher Szopko a, Klaus Helmke a, Christoph Stein c,* a
StaÈdtisches Krankenhaus MuÈnchen Bogenhausen, Akademisches Lehrkrankenhaus der Technischen UniversitaÈt MuÈnchen, IV. Medizinische Abteilung, Rheumatologie, Klinische Immunologie, 81925 Munich, Germany b Abteilung Statistik und Dokumentation, Max-Planck-Institut fuÈr Psychiatrie, 80804 Munich, Germany c Klinik fuÈr Anaesthesiologie und operative Intensivmedizin, UniversitaÈtsklinikum Benjamin Franklin, Freie UniversitaÈt Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany Received 19 February 1999; received in revised form 8 June 1999; accepted 17 June 1999
Abstract Intraarticular morphine inhibits pain after knee surgery without overt toxicity. This study examined intraarticular morphine in chronic arthritis. We undertook a randomized double-blind comparison between intraarticular morphine (3 mg), dexamethasone (4 mg) and saline (3 ml) in 44 patients with chronic in¯ammatory arthritis or osteoarthritis of the knee. Pain (the primary outcome measure) was assessed at rest and during activity for 6 days using a visual analog scale (VAS) and the McGill pain questionnaire. Before drug injections and on day 6 synovial leukocyte counts (the secondary outcome measure) were taken. During the ®rst 6 h after injection both morphine and dexamethasone signi®cantly reduced VAS and pain rating indices (PRI) in comparison to saline. Both substances also produced a signi®cant reduction of PRI compared to saline during the subsequent 5 days. No patient displayed untoward side effects. Synovial leukocyte counts were lower after morphine than after saline. In conclusion, intraarticular morphine produces analgesia of similar magnitude to dexamethasone and it may have antiin¯ammatory actions in chronic arthritis. q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. Keywords: Analgesics; Morphine; Antiin¯ammatory drugs; Steroids; Pain; Arthritis; Intra-articular Injections; Opioid receptors
1. Introduction
2. Methods
Locally applied opioids have antinociceptive and antiin¯ammatory actions in animals (Barber and Gottschlich, 1992; Stein, 1995; Wilson et al., 1996). In humans, intraarticular (i.a.) morphine produces potent inhibition of acute postoperative pain after knee surgery without overt toxicity (Kalso et al., 1997; Stein et al., 1997). Both the analgesic and antiin¯ammatory effects are apparently mediated by peripheral opioid receptors which have been identi®ed on peripheral sensory nerve terminals in rats (Stein, 1995) and in humans (Stein et al., 1996). Here we examined the analgesic and antiin¯ammatory effects of i.a. morphine in patients with chronic arthritis. These effects were compared to those of an i.a. steroid (dexamethasone) and to a placebo (saline) injection.
2.1. Patients
* Corresponding author. Tel.: 149-30-8445-2731; fax: 149-30-84454469. E-mail address: [email protected] (C. Stein)
The study protocol adhered to the ethical guidelines of the International Association for the Study of Pain, it was approved by our institutional ethical committee and written informed consent was obtained from each patient. We examined 52 patients with in¯ammatory (rheumatoid) arthritis (n 24) or osteoarthritis (n 28) according to the criteria established by the American College of Rheumatology (Altman et al., 1986; Arnett et al., 1988). Patients with bacterial synovitis (as determined by microbiological analysis of synovial ¯uid) or recent trauma to the knee joint were excluded (Table 1). Rheumatoid arthritis was de®ned by the presence of 4 or more of the following criteria: morning stiffness in and around joints lasting for at least 1 h; soft tissue swelling of 3 or more joint areas observed by a physician; swelling of the proximal interphalangeal, metacarpophalangeal, or wrist joints; symmetric joint swelling; rheumatoid nodules; presence of serum rheumatoid factor; synovial ¯uid leukocyte counts over 2000 cells/mm 3; radiographic erosions and/
0304-3959/99/$20.00 q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. PII: S 0304-395 9(99)00156-6
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or periarticular osteopenia in hand and/or wrist joints. The ®rst 4 criteria had to be present for at least 6 weeks. In addition, all in¯ammatory arthritis patients had an elevation of erythrocyte sedimentation rate and C-reactive protein, and a severely painful swollen knee joint. The osteoarthritis patients included idiopathic and secondary osteoarthritis, de®ned by the presence of knee pain plus at least 5 of the following criteria: age .50 years; morning stiffness ,30 min duration; crepitus on active motion; tenderness of the bony margins of the joint; bony enlargement on examination; lack of palpable synovial warmth; erythrocyte sedimentation rate ,40 mm/h; negative serum rheumatoid factor; viscous, clear synovial ¯uid with leukocyte counts under 2000 cells/mm 3; radiographic ®ndings (osteophytes, joint space narrowing, subchondral sclerosis).
measurements and the supplemental analgesic medication were recorded by the same blinded investigator at 1, 2, 3, 4 and 6 h. On each subsequent day the pain scores were obtained in the morning (between 7:00 and 9:00) and at night (between 17:00 and 19:00). Patients were asked to provide separate VAS ratings of their pain at rest [VAS (rest)] and during normal household activities [VAS (activity)]. Side effects (pruritus, paresthesia, urinary retention, nausea, vomiting, obstipation, dizziness, rash) and signs of dependence or addiction (drug craving, drug seeking, withdrawal) were recorded at the above time intervals.
2.2. Treatments
In eight patients (3 morphine- and 5 saline-treated) the data were incomplete. Because these patients dropped out of the study rather early (most of them within the ®rst day), we did not perform an intention to treat analysis. Thus, 18 dexamethasone-, 14 morphine- and 12 saline-treated patients were included in the statistical analysis. The score for the VAS was the distance (in mm) from the `no pain' end to the mark provided by the patient. The pain rating indices (PRI) were calculated for each category (sensory, affective, evaluative, miscellaneous) and the number of words chosen (NWC) to describe pain was counted (Melzack, 1975). Each patient's total consumption of supplementary analgesics over the 6 day observation period was recorded. To neutralize differences in baseline values and to avoid carryover effects resulting therefrom, individual pain scores, plasma parameters and synovial leukocyte counts after drug injection were normalized (i.e. divided by the patient's preinjection value) and expressed as percentage of baseline. To approach normal distribution of data, the arctan transformation was applied (ThoÈni, 1967; Dexter and Chestnut, 1995). Comparisons of pain scores were performed every hour (for the ®rst 6 h after injection) and once per day thereafter. For the latter analysis we calculated the means of the two pain scores taken on each day. A two-factorial multivariate analysis of covariance (MANCOVA) with repeated measures design and age as covariate was performed. Treatment was a `between-subjects factor' and time a `withinsubjects factor'. In case of signi®cant main and/or interaction effects in the analysis of variance, subsequent univariate F-tests were applied to identify the variables contributing to those effects. For variables exhibiting significant treatment and/or time effects, tests with contrasts followed to determine the respective treatment or time pairs with signi®cant differences. A two-factorial analysis of variance (ANOVA) was also performed for treatment and time differences in laboratory parameters. A nominal level of signi®cance of a 0:05 was accepted for testing main and interaction effects, and was reduced by the Bonferroni
All patients underwent ultrasonography of the knee joint immediately before cannulation of the joint for withdrawal of synovial ¯uid and subsequent drug injection. They were divided into three subgroups receiving one of the three treatments morphine, dexamethasone or saline in a randomized order. The resulting subgroups had the following sizes: dexamethasone (n 18); morphine (n 17); saline (n 17). These substances were prepared in syringes containing either normal saline, 3 mg morphine hydrochloride (Merck, Darmstadt, Germany), or 4 mg dexamethasone-21-dihydrogenphosphate suspension (Merck, Darmstadt, Germany), each in 3 ml saline. The doses were chosen on the basis of previous studies using i.a. morphine after knee surgery. In those studies, morphine doses between 0.5 and 6 mg were given in volumes of up to 40 ml saline (Stein et al., 1997). The dexamethasone preparation has a plasma half life of ca. 200 min and a biological half life of ca. 36±72 h. All solutions were of the same color, the syringes were coded and then given to the investigator who did not know their contents. The codes were broken upon completion of the study. All patients were allowed to take their usual supplemental medication as needed (oral acetylsalicylate up to 300 mg; ibuprofen up to 800 mg; diclofenac up to 200 mg daily). 2.3. Evaluation The patients were observed for 6 days. Before i.a. injections and at the end of the study, laboratory parameters (blood cell count; erythrocyte sedimentation rate; C-reactive protein; complement C3, C4; rheumatoid factor; synovial ¯uid leukocyte count) were assessed. Synovial ¯uid was obtained by aseptic puncture of the joint, heparinized, stained with methylene blue, and cells were counted using a Neubauer chamber. Before the injections, the patients were instructed in the use of a 100 mm visual analogue scale (VAS) (no pain to unbearable pain) and a German adaptation of the McGill Pain Questionnaire (MPQ) (Stein and Mendl, 1988), and baseline values were taken. After the injections these
2.4. Data analysis
A. Stein et al. / Pain 83 (1999) 525±532
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3. Results
(i.e. three patients per group). There were no signi®cant differences between groups in the total consumption of supplemental analgesics during the 6 day observation period. None of the patients reported any side effects, signs of dependence, drug seeking behavior or addiction.
3.1. Pain measurements
3.3. Laboratory parameters
The covariate `age' did not have any signi®cant effects on pain scores in any group and there were no signi®cant differences between in¯ammatory and osteoarthritis patients. During the ®rst 6 h after drug injection, MANCOVA indicated signi®cant main effects of `treatment' and `time' and a signi®cant `treatment by time' interaction effect (Wilks multivariate tests; effect of treatment: F 6; 76 3:48, signi®cance of F 0:004; effect of time: F 12; 30 7:28, signi®cance of F # 0:0001; effect of treatment by time: F 24; 60 1:87, signi®cance of F 0:026). These effects were identi®ed on the VAS scores (both rest and activity) and on the sensory PRI (univariate Ftests, P , 0:05). Therefore, we examined treatment (simple effects) and time differences of those scores. Compared to saline, patients treated with morphine showed a signi®cant reduction of sensory PRI (Fig. 1A) and VAS scores at rest (Fig. 1B) and activity (Fig. 1C) during the ®rst 6 h after injection (Table 2) (test with contrasts; P , 0:05). In comparison to saline, dexamethasone signi®cantly reduced the sensory PRI only towards the end of the 6 h interval (test with contrasts; P , 0:05). It also produced a signi®cant reduction of VAS scores at rest, but not during activity (Fig. 1B). During the subsequent 5 days after injection we found a signi®cant `treatment' effect (Wilks multivariate tests; effect of treatment: F 6; 76 2:67, signi®cance of F 0:025) on the sensory PRI only (univariate F-tests, P , 0:05) (Table 3). The analysis of simple effects showed that both morphine and dexamethasone signi®cantly reduced sensory PRI during the rest of the observation period, with the exception of day 4 (both) and day 5 (dexamethasone) (test with contrasts; P , 0:05). Both dexamethasone and morphine produced lower VAS values than saline, but these differences did not reach statistical signi®cance during days 2±6 after drug injection.
There were no signi®cant differences between groups in plasma levels of C-reactive protein, complement, leukocyte counts or erythrocyte sedimentation rate at any time (ANOVA). About one quarter of the patients (distributed equally among the groups) refused the second diagnostic cannulation of the joint. In the remaining patients, ANOVA indicated signi®cant time and treatment effects (P , 0:05) on synovial leukocyte counts. The ratio of synovial leukocyte counts after versus before i.a. injections was signi®cantly less in patients having received i.a. morphine (35 ^ 15%) compared to patients having received i.a. dexamethasone (66 ^ 11%) or i.a. saline (82 ^ 24%) (tests with contrasts; P , 0:05).
procedure whenever post-hoc tests were performed. Results are given as means ^ standard errors of the mean (SEM).
3.2. Supplemental medication and side effects Supplemental oral medication was taken by a total of nine patients who were distributed similarly among the groups Table 1 Demographic characteristics of patients Group
Dexamethasone
Morphine
Saline
N Sex (f/m) Age (years)
18 13/5 62.9 ^ 5.3 (27±96)
14 9/5 65.5 ^ 8.3 (24±83)
12 7/5 66.6 ^ 5.2 (42±88)
4. Discussion These results show that i.a. morphine produces potent analgesia in chronic arthritis and that morphine's effect may be even stronger than that of i.a. dexamethasone. In addition, i.a. morphine may have antiin¯ammatory actions, as evidenced by the decreased synovial leukocyte counts in both groups of patients. Consistent with previous studies (Kalso et al., 1997; Likar et al., 1997; Stein et al., 1997), we found no overt untoward side effects of i.a. morphine. Our ®ndings are in agreement with a large number of studies that have tested the analgesic ef®cacy of i.a. morphine after knee surgery (Stein et al., 1997) and with one report in patients with chronic osteoarthritis (Likar et al., 1997). Although some of these studies have not been able to detect such effects, the majority has shown potent and long-lasting analgesia (Kalso et al., 1997; Likar et al., 1997; Stein et al., 1997; Stein and Yassouridis, 1997). In the present study, pain-relieving effects were demonstrated by two different subjective measures, the VAS and the MPQ. The ®rst is designed to measure the intensity of pain, whereas the latter discriminates between the sensory and affective-evaluative dimensions of pain (Melzack, 1975). As one would anticipate with arthritic pain, generally considered of somatic nature, the MPQ descriptors chosen by the patients were mostly from the sensory category. Both PRI and VAS values were signi®cantly reduced by morphine and dexamethasone during the ®rst 6 h. During the subsequent 5 days, this reduction was signi®cant for PRI but not for VAS values. This may be due to the fact that age was a covariate in the calculation of P-values but not in the calculation of means for descriptive purposes. In general however, the data were internally consistent in that both pain scales yielded similar results.
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A. Stein et al. / Pain 83 (1999) 525±532
Fig. 1. Pain scores of patients receiving intraarticular morphine (B) dexamethasone (K) or saline (X). Values are (A) sensory pain rating indices (Melzack, 1975), (B) VAS at rest, and (C) VAS during activity, expressed as percentages of preinjection scores. Means and standard errors of the mean are shown. For signi®cant differences between the three treatments see Tables 2 and 3.
The analgesic effects of the i.a. drugs were not re¯ected in a decrease of supplemental intake of oral analgesic/antiin-
¯ammatory drugs. This is most probably due to the fact that none of the patients took large amounts of these substances,
8.89 5.80 5.06 4.67 4.20 3.96
28.33 20.48 18.83 17.57 15.00 13.46
51.22 39.76 37.37 35.43 33.15 32.70
VAS (rest) Baseline 1st hour 2nd hour 3rd hour 4th hour 6th hour
VAS (activity) Baseline 1st hour 2nd hour 3rd hour 4th hour 6th hour
100.00 83.47 82.43 76.70 67.75 60.44
100.00 72.07 72.20 71.44 63.24 56.06
100.00 70.58 61.90 58.36 52.94 47.90
0.00 9.48 12.84 11.31 8.11 6.34
0.00 6.24 7.67 8.51 8.23 7.25
0.00 6.24 6.06 5.56 5.47 5.87
(norm. val)
63.29 40.95 36.93 34.33 34.12 36.67
40.71 26.86 22.38 19.10 20.74 23.33
12.14 6.10 5.55 5.19 5.10 5.12
(orig. val)
(norm. val)
(orig. val)
100.00 64.79 58.83 54.68 54.38 57.48
100.00 64.89 56.22 51.98 53.01 56.27
100.00 49.60 43.79 40.06 39.89 39.66
(norm. val)
Mean
Mean
SEM
Mean
Mean
PR (sensory) Baseline 1st hour 2nd hour 3rd hour 4th hour 6th hour
Pain scores during the 1st day
Morphine (n 14) (2)
Dexamethasone (n 18) (1)
0.00 6.00 6.86 6.92 6.96 6.93
0.00 5.93 7.21 6.76 6.03 5.29
0.00 6.99 7.32 7.64 7.14 6.16
(norm. val)
SEM
40.13 38.13 36.00 35.04 33.83 31.71
32.38 29.21 27.42 27.54 25.63 25.29
11.00 7.21 7.62 8.29 7.79 7.63
(orig. val)
Mean
NaCl (n 12) (3)
100.00 102.58 98.65 89.78 93.10 89.65
100.00 96.72 89.69 95.75 90.68 85.81
100.00 67.01 71.43 82.27 87.90 90.56
(norm. val)
Mean
0.00 13.34 12.37 9.26 11.20 15.23
0.00 9.60 6.15 9.45 9.35 8.78
0.00 9.06 9.68 8.92 12.47 15.43
(norm. val)
SEM
3.40* 2.65 2.83 4.36* 3.28*
5.35* 4.30* 5.94* 4.73* 4.40*
2.66 3.34* 8.10* 9.29* 9.61*
Univariate F-tests (d.f. 2.40)
Effect of treatment
2/3 1/3, 2/3
2/3
1/3, 2/3 2/3 1/3, 2/3 1/3, 2/3 1/3, 2/3
2/3 2/3 1/3, 2/3 1/3, 2/3 1/3, 2/3
Test with contrasts
Sign. diff
Table 2 Original mean values and means ^ SEM of the normalized sensory pain rating indices (PRI) and visual analog scores (VAS) at rest and activity during the ®rst 6 h after intraarticular injection of dexamethasone, morphine or saline (NaCl). (*) denotes signi®cant F-values by the univariate F-tests in the analysis of covariance
A. Stein et al. / Pain 83 (1999) 525±532 529
8.89 3.77 4.16 4.68 5.17 5.33
28.33 13.15 15.51 17.35 19.89 21.28
51.22 31.81 31.73 32.39 34.76 37.34
VAS (rest) Baseline 2nd day 3rd day 4th day 5th day 6th day
VAS (activity) Baseline 2nd day 3rd day 4th day 5th day 6th day
100.00 58.32 60.98 66.18 72.66 75.10
100.00 58.08 70.42 76.29 81.81 86.14
100.00 43.21 45.50 54.19 61.79 61.95
0.00 5.97 8.25 9.13 10.14 9.86
0.00 9.36 14.07 15.01 13.86 14.70
0.00 6.58 8.71 9.40 9.19 8.90
(norm val)
63.29 38.64 38.68 40.57 38.19 37.01
40.71 25.46 26.24 27.33 25.88 25.44
12.14 5.29 5.48 6.06 5.81 5.74
(orig val)
(norm val)
(orig val)
100.00 59.66 58.74 64.37 61.74 57.04
100.00 61.81 71.26 68.41 63.64 58.93
100.00 41.90 45.28 49.38 46.66 45.61
(norm val)
Mean
Mean
SEM
Mean
Mean
PRI (sensory) Baseline 2nd day 3rd day 4th day 5th day 6th day
Pain scores during the next 5 days
Morphine (n 14) (2)
Dexamethasone (n 18) (1)
0.00 7.08 7.07 9.22 9.25 7.47
0.00 6.54 10.35 7.03 6.21 5.09
0.00 5.33 7.08 7.70 7.08 7.09
(norm val)
SEM
40.13 28.31 30.44 32.44 34.29 34.02
32.38 23.19 23.90 26.90 29.63 29.42
11.00 6.85 6.94 6.92 6.90 7.15
(orig val)
Mean
100.00 81.18 83.55 88.81 91.26 85.27
100.00 74.89 78.86 92.64 101.83 100.57
100.00 85.68 86.07 82.50 86.84 91.21
(norm val)
Mean
NaCl (n 12) (3)
0.00 16.78 14.27 13.55 15.63 12.86
0.00 8.70 9.53 8.64 8.16 9.33
0.00 16.34 18.30 14.59 16.64 18.83
(norm val)
SEM
1.61 1.91 1.65 1.64 2.00
0.65 0.06 0.83 2.47 2.88
7.13* 4.04* 2.59 3.60* 4.42*
Univariate F-tests (d.f. 2.37)
Effect of treatment
2/3 1/3, 2/3
1/3, 2/3 1/3, 2/3
Test with contrasts
Sign. diff.
Table 3 Original mean values and means ^ SEM of the normalized sensory pain rating indices (PRI) and visual analog scores (VAS) at rest and activity during the subsequent 5 days after intraarticular injection of dexamethasone, morphine or saline (NaCl). (*) Denotes signi®cant F-values by the univariate F-tests in the analysis of covariance
530 A. Stein et al. / Pain 83 (1999) 525±532
A. Stein et al. / Pain 83 (1999) 525±532
making it impossible to detect statistically signi®cant effects. For the same reason it is unlikely that these substances account for the observed differences in synovial leukocyte counts. What are the mechanisms of analgesic and antiin¯ammatory actions of i.a. morphine? Most probably, i.a. morphine activates opioid receptors on peripheral sensory nerve terminals (Stein, 1995; Stein et al., 1996). These receptors are synthesized in the dorsal root ganglia, they are axonally transported towards the nerve terminals and they can be activated by exogenous agonists as well as by endogenous opioid peptides expressed in in¯ammatory cells (Stein, 1995). Interestingly, local opioid analgesic effects are more pronounced in in¯amed than in non-in¯amed tissue. This may be related to an upregulation of peripheral opioid receptors (Hassan et al., 1993; SchaÈfer et al., 1995), to their enhanced coupling with G-proteins (Selley et al., 1993) and/ or to a disruption of the perineurial barrier, leading to a facilitated access for opioid agonists (Antonijevic et al., 1995). Opioids increase potassium and decrease calcium currents in dorsal root ganglion sensory neurons (Werz and Macdonald, 1982; Schroeder and McCleskey, 1993), they attenuate the excitability of the peripheral nociceptive terminal and the propagation of action potentials (Russell et al., 1987; Andreev et al., 1994), they inhibit the (calcium dependent) release of excitatory proin¯ammatory compounds (e.g. substance P) from peripheral sensory nerve endings (Brodin et al., 1983; Yaksh, 1988), they decrease plasma extravasation (Martinez et al., 1996), they inhibit ICAM-1 expression (Wilson et al., 1998) and they attenuate swelling, histological and radiographic parameters of experimental arthritis (Wilson et al., 1996). Opioid binding sites have also been demonstrated on immune cells and opioid-mediated modulation of their proliferation and several of their functions (e.g. chemotaxis, superoxide production, mast cell degranulation) has been reported (Bryant and Holaday, 1993). Together, these mechanisms may well account for both the antiin¯ammatory and analgesic actions of locally applied opioids. In agreement with previous studies (Khoury et al., 1992; Likar et al., 1997), we observed a long-lasting analgesic effect of i.a. morphine. The reasons for this prolonged duration of action are not yet clear. Our preliminary synovial leukocyte counts suggest antiin¯ammatory effects as a possibility. Such effects may preempt or delay the establishment of peripheral and, subsequently, central sensitization and thus prevent long-term excitatory effects (wind-up) (Woolf and Chong, 1993) and proin¯ammatory re¯ex mechanisms in the spinal cord (Sluka et al., 1994). Other possible explanations include low blood ¯ow to and hence low clearance from the knee joint, morphine's low lipid solubility and slow absorption into the circulation and analgesic effects of morphine metabolites. In knee surgery, doses between 0.5 mg and 6 mg of i.a. morphine have been used and shown to act locally within the joint, rather than by systemic absorption. This conclu-
531
sion was based on control groups receiving the same amount of morphine systemically (e.g. intravenously), on the measurement of plasma concentrations of morphine and on the complete absence of systemic side effects such as nausea, vomiting, dizziness, obstipation, signs of dependence or addiction (Kalso et al., 1997; Stein et al., 1997). Consistently, we did not observe any side effects attributable to the systemic absorption of morphine either, including signs of addiction or dependence. This is not surprising considering that the minimum effective dose of intravenous morphine for the treatment of severe (e.g. postoperative) pain is in the range of 10±15 mg for adults. Such doses are given several times per day in the postoperative situation without producing addicted patients. Thus, neither addiction nor dependence are a reasonable concern in arthritis patients receiving an injection of 3 mg morphine intraarticularly. In summary, i.a. morphine is an effective analgesic and possibly antiin¯ammatory treatment in chronic arthritis. Opioid receptors on peripheral terminals of primary afferent nerves most probably mediate morphine's effects. Whether i.a. morphine alone or in combination with steroids will represent a viable treatment option in in¯ammatory arthritis or osteoarthritis (especially in the long term) awaits further studies. In particular, the repeated administration of opioids needs to be investigated. Steroid antiin¯ammatory drugs have been administered intraarticularly for the treatment of various forms of painful chronic arthritis but these compounds have the potential for serious side effects (e.g. cartilage breakdown) that preclude frequent repeated injections and make it highly desirable to identify novel agents devoid of such effects (Ishikawa et al., 1984; Stefanich, 1986; Yamashita et al., 1986; Kongtawelert et al., 1989; Hochberg et al., 1995). So far, the absence of overt toxic side effects suggests that opioids may be a promising novel class of intraarticular agents in chronic arthritis. Moreover, these ®ndings may lead to the development of an entirely novel generation of analgesic and antiin¯ammatory drugs, possibly with disease-modifying properties in arthritis (Wilson et al., 1996). Such peripherally acting opioid analgesics should be devoid of central side effects such as respiratory depression, sedation, dependence or addiction. Acknowledgements We thank Mrs. J. Taylor and A. Aynur for secretarial assistance. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) and by NIH/NINDS. References Altman R, Asch E, Bloch D, et al. Development of criteria for the classi®cation and reporting of osteoarthritis. Arthritis Rheum 1986;29:1039± 1049. Andreev N, Urban L, Dray A. Opioids suppress spontaneous activity of polymodal nociceptors in rat paw skin induced by ultraviolet irradiation. Neuroscience 1994;58:793±798.
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®ne afferent units from in¯amed knee joint of the cat. Neurosci Lett 1987;76:107±112. SchaÈfer M, Imai Y, Uhl GR, Stein C. In¯ammation enhances peripheral mopioid receptor-mediated analgesia, but not m-opioid receptor transcription in dorsal root ganglia. Eur J Pharmacol 1995;279:165±169. Schroeder JE, McCleskey EW. Inhibition of Ca 21 currents by a mu-opioid in a de®ned subset of rat sensory neurons. J Neurosci 1993;13:867±873. Selley DE, Breivogel CS, Childers SR. Modi®cation of G protein-coupled functions by low pH pretreatment of membranes from NG108-15 cells: increase in opioid agonist ef®cacy by decreased inactivation of G proteins. Mol Pharmacol 1993;44:731±741. Sluka KA, Lawand NB, Westlund KN. Joint in¯ammation is reduced by dorsal rhizotomy and not by sympathectomy or spinal cord transection. Ann Rheum Dis 1994;53:309±314. Stefanich RJ. Intraarticular corticosteroids in treatment of osteoarthritis. Orthop Rev 1986;15:65±71. Stein C, Mendl G. The German counterpart to McGill pain questionnaire. Pain 1988;32:251±255. Stein C, Yassouridis A. Peripheral morphine analgesia [editorial]. Pain 1997;71:119±121. Stein C, P¯uÈger M, Yassouridis A, Hoelzl J, Lehrberger K, Welte C, Hassan AHS. No tolerance to peripheral morphine analgesia in presence of opioid expression in in¯amed synovia. J Clin Invest 1996;98:793±799. Stein C, SchaÈfer M, Cabot PJ, Carter L, Zhang Q, Zhou L, Gasior M. Peripheral opioid analgesia. Pain Rev 1997;4:171±185. Stein C. The control of pain in peripheral tissue by opioids. N Eng J Med 1995;332:1685±1690. ThoÈni H. Transformation of variables used in the analysis of experimental and observational data. A review, Statistical Laboratory Iowa State University. Tech Rep 1967;7. Werz MA, Macdonald RL. Heterogeneous sensitivity of cultured dorsal root ganglion neurones to opioid peptides selective for mu- and deltaopiate receptors. Nature 1982;299:730±733. Wilson JL, Nayanar V, Walker JS. The site of anti-arthritic action of the kopioid U-50,488H, in adjuvant arthritis: importance of local administration. Br J Pharmacol 1996;118:1754±1760. Wilson JL, Walker JS, Antoon JS, Perry MA. Intercellular adhesion molecule-1 expression in adjuvant arthritis in rats: inhibition by kappaopioid agonist but not by NSAID. J Rheumatol 1998;25:499±505. Woolf CJ, Chong MS. Preemptive analgesia - treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993;77:362±379. Yaksh TL. Substance P release from knee joint afferent terminals: modulation by opioids. Brain Res 1988;458:319±324. Yamashita K, Yada H, Irimura K, Hayashi T, Morinaga H, Morita K. A ®fty-two-week chronic toxicity study of halopredone acetate (THS201) in dogs. J Toxicol Sci 1986;11:81±106.
Intraarticular morphine versus dexamethasone in chronic arthritis Andreas Stein a, Alexander Yassouridis b, Christopher Szopko a, Klaus Helmke a, Christoph Stein c,* a
StaÈdtisches Krankenhaus MuÈnchen Bogenhausen, Akademisches Lehrkrankenhaus der Technischen UniversitaÈt MuÈnchen, IV. Medizinische Abteilung, Rheumatologie, Klinische Immunologie, 81925 Munich, Germany b Abteilung Statistik und Dokumentation, Max-Planck-Institut fuÈr Psychiatrie, 80804 Munich, Germany c Klinik fuÈr Anaesthesiologie und operative Intensivmedizin, UniversitaÈtsklinikum Benjamin Franklin, Freie UniversitaÈt Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany Received 19 February 1999; received in revised form 8 June 1999; accepted 17 June 1999
Abstract Intraarticular morphine inhibits pain after knee surgery without overt toxicity. This study examined intraarticular morphine in chronic arthritis. We undertook a randomized double-blind comparison between intraarticular morphine (3 mg), dexamethasone (4 mg) and saline (3 ml) in 44 patients with chronic in¯ammatory arthritis or osteoarthritis of the knee. Pain (the primary outcome measure) was assessed at rest and during activity for 6 days using a visual analog scale (VAS) and the McGill pain questionnaire. Before drug injections and on day 6 synovial leukocyte counts (the secondary outcome measure) were taken. During the ®rst 6 h after injection both morphine and dexamethasone signi®cantly reduced VAS and pain rating indices (PRI) in comparison to saline. Both substances also produced a signi®cant reduction of PRI compared to saline during the subsequent 5 days. No patient displayed untoward side effects. Synovial leukocyte counts were lower after morphine than after saline. In conclusion, intraarticular morphine produces analgesia of similar magnitude to dexamethasone and it may have antiin¯ammatory actions in chronic arthritis. q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. Keywords: Analgesics; Morphine; Antiin¯ammatory drugs; Steroids; Pain; Arthritis; Intra-articular Injections; Opioid receptors
1. Introduction
2. Methods
Locally applied opioids have antinociceptive and antiin¯ammatory actions in animals (Barber and Gottschlich, 1992; Stein, 1995; Wilson et al., 1996). In humans, intraarticular (i.a.) morphine produces potent inhibition of acute postoperative pain after knee surgery without overt toxicity (Kalso et al., 1997; Stein et al., 1997). Both the analgesic and antiin¯ammatory effects are apparently mediated by peripheral opioid receptors which have been identi®ed on peripheral sensory nerve terminals in rats (Stein, 1995) and in humans (Stein et al., 1996). Here we examined the analgesic and antiin¯ammatory effects of i.a. morphine in patients with chronic arthritis. These effects were compared to those of an i.a. steroid (dexamethasone) and to a placebo (saline) injection.
2.1. Patients
* Corresponding author. Tel.: 149-30-8445-2731; fax: 149-30-84454469. E-mail address: [email protected] (C. Stein)
The study protocol adhered to the ethical guidelines of the International Association for the Study of Pain, it was approved by our institutional ethical committee and written informed consent was obtained from each patient. We examined 52 patients with in¯ammatory (rheumatoid) arthritis (n 24) or osteoarthritis (n 28) according to the criteria established by the American College of Rheumatology (Altman et al., 1986; Arnett et al., 1988). Patients with bacterial synovitis (as determined by microbiological analysis of synovial ¯uid) or recent trauma to the knee joint were excluded (Table 1). Rheumatoid arthritis was de®ned by the presence of 4 or more of the following criteria: morning stiffness in and around joints lasting for at least 1 h; soft tissue swelling of 3 or more joint areas observed by a physician; swelling of the proximal interphalangeal, metacarpophalangeal, or wrist joints; symmetric joint swelling; rheumatoid nodules; presence of serum rheumatoid factor; synovial ¯uid leukocyte counts over 2000 cells/mm 3; radiographic erosions and/
0304-3959/99/$20.00 q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. PII: S 0304-395 9(99)00156-6
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or periarticular osteopenia in hand and/or wrist joints. The ®rst 4 criteria had to be present for at least 6 weeks. In addition, all in¯ammatory arthritis patients had an elevation of erythrocyte sedimentation rate and C-reactive protein, and a severely painful swollen knee joint. The osteoarthritis patients included idiopathic and secondary osteoarthritis, de®ned by the presence of knee pain plus at least 5 of the following criteria: age .50 years; morning stiffness ,30 min duration; crepitus on active motion; tenderness of the bony margins of the joint; bony enlargement on examination; lack of palpable synovial warmth; erythrocyte sedimentation rate ,40 mm/h; negative serum rheumatoid factor; viscous, clear synovial ¯uid with leukocyte counts under 2000 cells/mm 3; radiographic ®ndings (osteophytes, joint space narrowing, subchondral sclerosis).
measurements and the supplemental analgesic medication were recorded by the same blinded investigator at 1, 2, 3, 4 and 6 h. On each subsequent day the pain scores were obtained in the morning (between 7:00 and 9:00) and at night (between 17:00 and 19:00). Patients were asked to provide separate VAS ratings of their pain at rest [VAS (rest)] and during normal household activities [VAS (activity)]. Side effects (pruritus, paresthesia, urinary retention, nausea, vomiting, obstipation, dizziness, rash) and signs of dependence or addiction (drug craving, drug seeking, withdrawal) were recorded at the above time intervals.
2.2. Treatments
In eight patients (3 morphine- and 5 saline-treated) the data were incomplete. Because these patients dropped out of the study rather early (most of them within the ®rst day), we did not perform an intention to treat analysis. Thus, 18 dexamethasone-, 14 morphine- and 12 saline-treated patients were included in the statistical analysis. The score for the VAS was the distance (in mm) from the `no pain' end to the mark provided by the patient. The pain rating indices (PRI) were calculated for each category (sensory, affective, evaluative, miscellaneous) and the number of words chosen (NWC) to describe pain was counted (Melzack, 1975). Each patient's total consumption of supplementary analgesics over the 6 day observation period was recorded. To neutralize differences in baseline values and to avoid carryover effects resulting therefrom, individual pain scores, plasma parameters and synovial leukocyte counts after drug injection were normalized (i.e. divided by the patient's preinjection value) and expressed as percentage of baseline. To approach normal distribution of data, the arctan transformation was applied (ThoÈni, 1967; Dexter and Chestnut, 1995). Comparisons of pain scores were performed every hour (for the ®rst 6 h after injection) and once per day thereafter. For the latter analysis we calculated the means of the two pain scores taken on each day. A two-factorial multivariate analysis of covariance (MANCOVA) with repeated measures design and age as covariate was performed. Treatment was a `between-subjects factor' and time a `withinsubjects factor'. In case of signi®cant main and/or interaction effects in the analysis of variance, subsequent univariate F-tests were applied to identify the variables contributing to those effects. For variables exhibiting significant treatment and/or time effects, tests with contrasts followed to determine the respective treatment or time pairs with signi®cant differences. A two-factorial analysis of variance (ANOVA) was also performed for treatment and time differences in laboratory parameters. A nominal level of signi®cance of a 0:05 was accepted for testing main and interaction effects, and was reduced by the Bonferroni
All patients underwent ultrasonography of the knee joint immediately before cannulation of the joint for withdrawal of synovial ¯uid and subsequent drug injection. They were divided into three subgroups receiving one of the three treatments morphine, dexamethasone or saline in a randomized order. The resulting subgroups had the following sizes: dexamethasone (n 18); morphine (n 17); saline (n 17). These substances were prepared in syringes containing either normal saline, 3 mg morphine hydrochloride (Merck, Darmstadt, Germany), or 4 mg dexamethasone-21-dihydrogenphosphate suspension (Merck, Darmstadt, Germany), each in 3 ml saline. The doses were chosen on the basis of previous studies using i.a. morphine after knee surgery. In those studies, morphine doses between 0.5 and 6 mg were given in volumes of up to 40 ml saline (Stein et al., 1997). The dexamethasone preparation has a plasma half life of ca. 200 min and a biological half life of ca. 36±72 h. All solutions were of the same color, the syringes were coded and then given to the investigator who did not know their contents. The codes were broken upon completion of the study. All patients were allowed to take their usual supplemental medication as needed (oral acetylsalicylate up to 300 mg; ibuprofen up to 800 mg; diclofenac up to 200 mg daily). 2.3. Evaluation The patients were observed for 6 days. Before i.a. injections and at the end of the study, laboratory parameters (blood cell count; erythrocyte sedimentation rate; C-reactive protein; complement C3, C4; rheumatoid factor; synovial ¯uid leukocyte count) were assessed. Synovial ¯uid was obtained by aseptic puncture of the joint, heparinized, stained with methylene blue, and cells were counted using a Neubauer chamber. Before the injections, the patients were instructed in the use of a 100 mm visual analogue scale (VAS) (no pain to unbearable pain) and a German adaptation of the McGill Pain Questionnaire (MPQ) (Stein and Mendl, 1988), and baseline values were taken. After the injections these
2.4. Data analysis
A. Stein et al. / Pain 83 (1999) 525±532
527
3. Results
(i.e. three patients per group). There were no signi®cant differences between groups in the total consumption of supplemental analgesics during the 6 day observation period. None of the patients reported any side effects, signs of dependence, drug seeking behavior or addiction.
3.1. Pain measurements
3.3. Laboratory parameters
The covariate `age' did not have any signi®cant effects on pain scores in any group and there were no signi®cant differences between in¯ammatory and osteoarthritis patients. During the ®rst 6 h after drug injection, MANCOVA indicated signi®cant main effects of `treatment' and `time' and a signi®cant `treatment by time' interaction effect (Wilks multivariate tests; effect of treatment: F 6; 76 3:48, signi®cance of F 0:004; effect of time: F 12; 30 7:28, signi®cance of F # 0:0001; effect of treatment by time: F 24; 60 1:87, signi®cance of F 0:026). These effects were identi®ed on the VAS scores (both rest and activity) and on the sensory PRI (univariate Ftests, P , 0:05). Therefore, we examined treatment (simple effects) and time differences of those scores. Compared to saline, patients treated with morphine showed a signi®cant reduction of sensory PRI (Fig. 1A) and VAS scores at rest (Fig. 1B) and activity (Fig. 1C) during the ®rst 6 h after injection (Table 2) (test with contrasts; P , 0:05). In comparison to saline, dexamethasone signi®cantly reduced the sensory PRI only towards the end of the 6 h interval (test with contrasts; P , 0:05). It also produced a signi®cant reduction of VAS scores at rest, but not during activity (Fig. 1B). During the subsequent 5 days after injection we found a signi®cant `treatment' effect (Wilks multivariate tests; effect of treatment: F 6; 76 2:67, signi®cance of F 0:025) on the sensory PRI only (univariate F-tests, P , 0:05) (Table 3). The analysis of simple effects showed that both morphine and dexamethasone signi®cantly reduced sensory PRI during the rest of the observation period, with the exception of day 4 (both) and day 5 (dexamethasone) (test with contrasts; P , 0:05). Both dexamethasone and morphine produced lower VAS values than saline, but these differences did not reach statistical signi®cance during days 2±6 after drug injection.
There were no signi®cant differences between groups in plasma levels of C-reactive protein, complement, leukocyte counts or erythrocyte sedimentation rate at any time (ANOVA). About one quarter of the patients (distributed equally among the groups) refused the second diagnostic cannulation of the joint. In the remaining patients, ANOVA indicated signi®cant time and treatment effects (P , 0:05) on synovial leukocyte counts. The ratio of synovial leukocyte counts after versus before i.a. injections was signi®cantly less in patients having received i.a. morphine (35 ^ 15%) compared to patients having received i.a. dexamethasone (66 ^ 11%) or i.a. saline (82 ^ 24%) (tests with contrasts; P , 0:05).
procedure whenever post-hoc tests were performed. Results are given as means ^ standard errors of the mean (SEM).
3.2. Supplemental medication and side effects Supplemental oral medication was taken by a total of nine patients who were distributed similarly among the groups Table 1 Demographic characteristics of patients Group
Dexamethasone
Morphine
Saline
N Sex (f/m) Age (years)
18 13/5 62.9 ^ 5.3 (27±96)
14 9/5 65.5 ^ 8.3 (24±83)
12 7/5 66.6 ^ 5.2 (42±88)
4. Discussion These results show that i.a. morphine produces potent analgesia in chronic arthritis and that morphine's effect may be even stronger than that of i.a. dexamethasone. In addition, i.a. morphine may have antiin¯ammatory actions, as evidenced by the decreased synovial leukocyte counts in both groups of patients. Consistent with previous studies (Kalso et al., 1997; Likar et al., 1997; Stein et al., 1997), we found no overt untoward side effects of i.a. morphine. Our ®ndings are in agreement with a large number of studies that have tested the analgesic ef®cacy of i.a. morphine after knee surgery (Stein et al., 1997) and with one report in patients with chronic osteoarthritis (Likar et al., 1997). Although some of these studies have not been able to detect such effects, the majority has shown potent and long-lasting analgesia (Kalso et al., 1997; Likar et al., 1997; Stein et al., 1997; Stein and Yassouridis, 1997). In the present study, pain-relieving effects were demonstrated by two different subjective measures, the VAS and the MPQ. The ®rst is designed to measure the intensity of pain, whereas the latter discriminates between the sensory and affective-evaluative dimensions of pain (Melzack, 1975). As one would anticipate with arthritic pain, generally considered of somatic nature, the MPQ descriptors chosen by the patients were mostly from the sensory category. Both PRI and VAS values were signi®cantly reduced by morphine and dexamethasone during the ®rst 6 h. During the subsequent 5 days, this reduction was signi®cant for PRI but not for VAS values. This may be due to the fact that age was a covariate in the calculation of P-values but not in the calculation of means for descriptive purposes. In general however, the data were internally consistent in that both pain scales yielded similar results.
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A. Stein et al. / Pain 83 (1999) 525±532
Fig. 1. Pain scores of patients receiving intraarticular morphine (B) dexamethasone (K) or saline (X). Values are (A) sensory pain rating indices (Melzack, 1975), (B) VAS at rest, and (C) VAS during activity, expressed as percentages of preinjection scores. Means and standard errors of the mean are shown. For signi®cant differences between the three treatments see Tables 2 and 3.
The analgesic effects of the i.a. drugs were not re¯ected in a decrease of supplemental intake of oral analgesic/antiin-
¯ammatory drugs. This is most probably due to the fact that none of the patients took large amounts of these substances,
8.89 5.80 5.06 4.67 4.20 3.96
28.33 20.48 18.83 17.57 15.00 13.46
51.22 39.76 37.37 35.43 33.15 32.70
VAS (rest) Baseline 1st hour 2nd hour 3rd hour 4th hour 6th hour
VAS (activity) Baseline 1st hour 2nd hour 3rd hour 4th hour 6th hour
100.00 83.47 82.43 76.70 67.75 60.44
100.00 72.07 72.20 71.44 63.24 56.06
100.00 70.58 61.90 58.36 52.94 47.90
0.00 9.48 12.84 11.31 8.11 6.34
0.00 6.24 7.67 8.51 8.23 7.25
0.00 6.24 6.06 5.56 5.47 5.87
(norm. val)
63.29 40.95 36.93 34.33 34.12 36.67
40.71 26.86 22.38 19.10 20.74 23.33
12.14 6.10 5.55 5.19 5.10 5.12
(orig. val)
(norm. val)
(orig. val)
100.00 64.79 58.83 54.68 54.38 57.48
100.00 64.89 56.22 51.98 53.01 56.27
100.00 49.60 43.79 40.06 39.89 39.66
(norm. val)
Mean
Mean
SEM
Mean
Mean
PR (sensory) Baseline 1st hour 2nd hour 3rd hour 4th hour 6th hour
Pain scores during the 1st day
Morphine (n 14) (2)
Dexamethasone (n 18) (1)
0.00 6.00 6.86 6.92 6.96 6.93
0.00 5.93 7.21 6.76 6.03 5.29
0.00 6.99 7.32 7.64 7.14 6.16
(norm. val)
SEM
40.13 38.13 36.00 35.04 33.83 31.71
32.38 29.21 27.42 27.54 25.63 25.29
11.00 7.21 7.62 8.29 7.79 7.63
(orig. val)
Mean
NaCl (n 12) (3)
100.00 102.58 98.65 89.78 93.10 89.65
100.00 96.72 89.69 95.75 90.68 85.81
100.00 67.01 71.43 82.27 87.90 90.56
(norm. val)
Mean
0.00 13.34 12.37 9.26 11.20 15.23
0.00 9.60 6.15 9.45 9.35 8.78
0.00 9.06 9.68 8.92 12.47 15.43
(norm. val)
SEM
3.40* 2.65 2.83 4.36* 3.28*
5.35* 4.30* 5.94* 4.73* 4.40*
2.66 3.34* 8.10* 9.29* 9.61*
Univariate F-tests (d.f. 2.40)
Effect of treatment
2/3 1/3, 2/3
2/3
1/3, 2/3 2/3 1/3, 2/3 1/3, 2/3 1/3, 2/3
2/3 2/3 1/3, 2/3 1/3, 2/3 1/3, 2/3
Test with contrasts
Sign. diff
Table 2 Original mean values and means ^ SEM of the normalized sensory pain rating indices (PRI) and visual analog scores (VAS) at rest and activity during the ®rst 6 h after intraarticular injection of dexamethasone, morphine or saline (NaCl). (*) denotes signi®cant F-values by the univariate F-tests in the analysis of covariance
A. Stein et al. / Pain 83 (1999) 525±532 529
8.89 3.77 4.16 4.68 5.17 5.33
28.33 13.15 15.51 17.35 19.89 21.28
51.22 31.81 31.73 32.39 34.76 37.34
VAS (rest) Baseline 2nd day 3rd day 4th day 5th day 6th day
VAS (activity) Baseline 2nd day 3rd day 4th day 5th day 6th day
100.00 58.32 60.98 66.18 72.66 75.10
100.00 58.08 70.42 76.29 81.81 86.14
100.00 43.21 45.50 54.19 61.79 61.95
0.00 5.97 8.25 9.13 10.14 9.86
0.00 9.36 14.07 15.01 13.86 14.70
0.00 6.58 8.71 9.40 9.19 8.90
(norm val)
63.29 38.64 38.68 40.57 38.19 37.01
40.71 25.46 26.24 27.33 25.88 25.44
12.14 5.29 5.48 6.06 5.81 5.74
(orig val)
(norm val)
(orig val)
100.00 59.66 58.74 64.37 61.74 57.04
100.00 61.81 71.26 68.41 63.64 58.93
100.00 41.90 45.28 49.38 46.66 45.61
(norm val)
Mean
Mean
SEM
Mean
Mean
PRI (sensory) Baseline 2nd day 3rd day 4th day 5th day 6th day
Pain scores during the next 5 days
Morphine (n 14) (2)
Dexamethasone (n 18) (1)
0.00 7.08 7.07 9.22 9.25 7.47
0.00 6.54 10.35 7.03 6.21 5.09
0.00 5.33 7.08 7.70 7.08 7.09
(norm val)
SEM
40.13 28.31 30.44 32.44 34.29 34.02
32.38 23.19 23.90 26.90 29.63 29.42
11.00 6.85 6.94 6.92 6.90 7.15
(orig val)
Mean
100.00 81.18 83.55 88.81 91.26 85.27
100.00 74.89 78.86 92.64 101.83 100.57
100.00 85.68 86.07 82.50 86.84 91.21
(norm val)
Mean
NaCl (n 12) (3)
0.00 16.78 14.27 13.55 15.63 12.86
0.00 8.70 9.53 8.64 8.16 9.33
0.00 16.34 18.30 14.59 16.64 18.83
(norm val)
SEM
1.61 1.91 1.65 1.64 2.00
0.65 0.06 0.83 2.47 2.88
7.13* 4.04* 2.59 3.60* 4.42*
Univariate F-tests (d.f. 2.37)
Effect of treatment
2/3 1/3, 2/3
1/3, 2/3 1/3, 2/3
Test with contrasts
Sign. diff.
Table 3 Original mean values and means ^ SEM of the normalized sensory pain rating indices (PRI) and visual analog scores (VAS) at rest and activity during the subsequent 5 days after intraarticular injection of dexamethasone, morphine or saline (NaCl). (*) Denotes signi®cant F-values by the univariate F-tests in the analysis of covariance
530 A. Stein et al. / Pain 83 (1999) 525±532
A. Stein et al. / Pain 83 (1999) 525±532
making it impossible to detect statistically signi®cant effects. For the same reason it is unlikely that these substances account for the observed differences in synovial leukocyte counts. What are the mechanisms of analgesic and antiin¯ammatory actions of i.a. morphine? Most probably, i.a. morphine activates opioid receptors on peripheral sensory nerve terminals (Stein, 1995; Stein et al., 1996). These receptors are synthesized in the dorsal root ganglia, they are axonally transported towards the nerve terminals and they can be activated by exogenous agonists as well as by endogenous opioid peptides expressed in in¯ammatory cells (Stein, 1995). Interestingly, local opioid analgesic effects are more pronounced in in¯amed than in non-in¯amed tissue. This may be related to an upregulation of peripheral opioid receptors (Hassan et al., 1993; SchaÈfer et al., 1995), to their enhanced coupling with G-proteins (Selley et al., 1993) and/ or to a disruption of the perineurial barrier, leading to a facilitated access for opioid agonists (Antonijevic et al., 1995). Opioids increase potassium and decrease calcium currents in dorsal root ganglion sensory neurons (Werz and Macdonald, 1982; Schroeder and McCleskey, 1993), they attenuate the excitability of the peripheral nociceptive terminal and the propagation of action potentials (Russell et al., 1987; Andreev et al., 1994), they inhibit the (calcium dependent) release of excitatory proin¯ammatory compounds (e.g. substance P) from peripheral sensory nerve endings (Brodin et al., 1983; Yaksh, 1988), they decrease plasma extravasation (Martinez et al., 1996), they inhibit ICAM-1 expression (Wilson et al., 1998) and they attenuate swelling, histological and radiographic parameters of experimental arthritis (Wilson et al., 1996). Opioid binding sites have also been demonstrated on immune cells and opioid-mediated modulation of their proliferation and several of their functions (e.g. chemotaxis, superoxide production, mast cell degranulation) has been reported (Bryant and Holaday, 1993). Together, these mechanisms may well account for both the antiin¯ammatory and analgesic actions of locally applied opioids. In agreement with previous studies (Khoury et al., 1992; Likar et al., 1997), we observed a long-lasting analgesic effect of i.a. morphine. The reasons for this prolonged duration of action are not yet clear. Our preliminary synovial leukocyte counts suggest antiin¯ammatory effects as a possibility. Such effects may preempt or delay the establishment of peripheral and, subsequently, central sensitization and thus prevent long-term excitatory effects (wind-up) (Woolf and Chong, 1993) and proin¯ammatory re¯ex mechanisms in the spinal cord (Sluka et al., 1994). Other possible explanations include low blood ¯ow to and hence low clearance from the knee joint, morphine's low lipid solubility and slow absorption into the circulation and analgesic effects of morphine metabolites. In knee surgery, doses between 0.5 mg and 6 mg of i.a. morphine have been used and shown to act locally within the joint, rather than by systemic absorption. This conclu-
531
sion was based on control groups receiving the same amount of morphine systemically (e.g. intravenously), on the measurement of plasma concentrations of morphine and on the complete absence of systemic side effects such as nausea, vomiting, dizziness, obstipation, signs of dependence or addiction (Kalso et al., 1997; Stein et al., 1997). Consistently, we did not observe any side effects attributable to the systemic absorption of morphine either, including signs of addiction or dependence. This is not surprising considering that the minimum effective dose of intravenous morphine for the treatment of severe (e.g. postoperative) pain is in the range of 10±15 mg for adults. Such doses are given several times per day in the postoperative situation without producing addicted patients. Thus, neither addiction nor dependence are a reasonable concern in arthritis patients receiving an injection of 3 mg morphine intraarticularly. In summary, i.a. morphine is an effective analgesic and possibly antiin¯ammatory treatment in chronic arthritis. Opioid receptors on peripheral terminals of primary afferent nerves most probably mediate morphine's effects. Whether i.a. morphine alone or in combination with steroids will represent a viable treatment option in in¯ammatory arthritis or osteoarthritis (especially in the long term) awaits further studies. In particular, the repeated administration of opioids needs to be investigated. Steroid antiin¯ammatory drugs have been administered intraarticularly for the treatment of various forms of painful chronic arthritis but these compounds have the potential for serious side effects (e.g. cartilage breakdown) that preclude frequent repeated injections and make it highly desirable to identify novel agents devoid of such effects (Ishikawa et al., 1984; Stefanich, 1986; Yamashita et al., 1986; Kongtawelert et al., 1989; Hochberg et al., 1995). So far, the absence of overt toxic side effects suggests that opioids may be a promising novel class of intraarticular agents in chronic arthritis. Moreover, these ®ndings may lead to the development of an entirely novel generation of analgesic and antiin¯ammatory drugs, possibly with disease-modifying properties in arthritis (Wilson et al., 1996). Such peripherally acting opioid analgesics should be devoid of central side effects such as respiratory depression, sedation, dependence or addiction. Acknowledgements We thank Mrs. J. Taylor and A. Aynur for secretarial assistance. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) and by NIH/NINDS. References Altman R, Asch E, Bloch D, et al. Development of criteria for the classi®cation and reporting of osteoarthritis. Arthritis Rheum 1986;29:1039± 1049. Andreev N, Urban L, Dray A. Opioids suppress spontaneous activity of polymodal nociceptors in rat paw skin induced by ultraviolet irradiation. Neuroscience 1994;58:793±798.
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