- Email: [email protected]
Randomised controlled trial with medical leeches for osteoarthritis of the knee
Complementary Therapies in Medicine (2012) 20, 1—7
Available online at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/ctim
Randomised controlled trial with medical leeches for osteoarthritis of the knee Rainer Stange a,∗, Claudia Moser a, W. Hopfenmueller b, U. Mansmann c, M. Buehring a, B. Uehleke a a
Charité - Universitaetsmedizin Berlin - Campus Benjamin Franklin, Department for Natural Medicine, Koenigstr. 63, D-14109 Berlin, Germany b Charité - Universitaetsmedizin Berlin, Institute for Biometry and Clinical Epidemiology, Hindenburgdamm 30, D-12203 Berlin, Germany c Ludwig-Maximilian-University Munich, Institute for Medical Data Processing, Biometry und Epidemiology, Germany Available online 15 November 2011
KEYWORDS Randomised controlled trial; Complementary medicine; Leeches; Leeching; Hirudinea; Hirudo medicinalis; Osteoarthritis of the knee; Lequesne’s index; VAS
∗
Summary Objectives: To evaluate the possible efficacy of medical leeches (Hirudo medicinalis) in the treatment of patients with active osteoarthritis of the knee. Design: Unblinded, randomised controlled trial with outpatients in a crossover design with single interventions of either leeches or transcutaneous electrical nerve stimulation (TENS) as comparator. Main outcome measures: Change in Lequesne’s combined index for pain and function and change (L.I.) and overall assessment of complaints by visual analog scale (VAS). Cross-over at day 42, with further observation period of 21 days. Results: 52 out of 72 screened patients were randomised (intent to treat) to initial treatment with either eight leeches (group 1: 27 patients) or TENS (group 2: 25 patients). Due to phase effects, confirmatory evaluation had to be restricted to the first period. Between days 0 and 21, we observed highly significant (p < 0.001) improvements for means of Lequesne’s index from 12.07 to 9.37 and for VAS from 5.89 to 4.16 cm for leeches, but no significant differences for TENS. Effect size as group difference was -2.50 for L.I. (95% confidence interval −3.88 to −1.11), resp. −1.86 cm for VAS (95% confidence interval −2.85 to −0.87 cm). 12 patients (5 group1, 7 group 2) did not finish the trial, mostly due to non-compliance (6). No serious adverse effects were observed. Conclusions: Single leech therapy showed significant, relevant and sustaining effects, comparable to other trials with leeches. The method deserves further research, esp. into mechanisms of possible specific effects and optimization of dosing by number of leeches and possible repeats. © 2011 Elsevier Ltd. All rights reserved.
Corresponding author. Tel.: +49 3080505 690; fax: +49 30 80505 692. E-mail addresses: [email protected], [email protected] (R. Stange).
0965-2299/$ — see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctim.2011.10.006
2
Introduction Over several thousand years, different medical cultures have been making use of treatment with leeches.1,2 In the 17th and 18th centuries, this treatment was widespread, and there seemed to be no limits as to frequency, topic extent, and number of leeches used. Even though leeching and other so-called humoral therapies were very popular and got established as a regime in naturopathy in different countries, balanced clinical assessments and controlled clinical studies are still missing.3—6 Today there is a striking disproportion between frequency of application and clinical documentation as it is well-known from other therapies. Despite intensive data retrieval (esp. Medline; keywords: leeches, leech, leech therapy, bloodletting, Hirudinea, and Hirudo officinalis) and inquiries at the manufactures and users of medicinal leeches, it was at the time of planning this study not possible to find any accurate planned clinical study or surveillance study except one7 and a rather anecdotal report.8 Next to varicosis, osteoarthritis is one of the most frequent and clinically remarkable indications for leeching. We conducted a randomised clinical study to investigate the therapeutical significance of a single treatment with medicinal leeches in patients with uncomplicated active osteoarthritis of the knee using validated measuring instruments.
Materials and methods Patients Patients with osteoarthritis of one or both knees with stadium II according to the classification of Jaeger and Wirth were included.9 With both-sided osteoarthritis, patients could be included, if a clear difference between sides could be found, in which case only the more affected knee was treated. Main exclusion criteria were undetermined complaints of both knees, chronic inflammatory diseases like rheumatoid arthritis, anemia (hemoglobin less than 12.0 g/dl for men, resp. 10.0 g/dl for women), malign and consumptive diseases, and regular intake of anticoagulant drugs as well as low dose acetylicsalicylic acid. The patients were asked for voluntary participation, and written consent was requested. The study was approved by the ethics committee of the Freie Universitaet Berlin, Germany.
Leeches and treatment The medicinal leeches were imported from a Turkish cultivation by a German import company (Moser Blutegelhandel, Fellbach, Germany). After arrival, leeches were kept in daily changed tap water for at least 48 h (minimum volume 1 l/leech) before application. Therapy consisted of a single application of eight medicinal leeches. Sites for bites were above and below the patella as well as medially and laterally in projection to the joint cavity. There was no preparation of the skin. As it is not always possible to let leeches bite, a minimum of six and a maximum of eight bites per treatment was considered to be a per protocol therapy. This minimum was achieved in all randomised patients. After biting, the
R. Stange et al. leeches were left as long as possible in their original position while knees were immobilized. When leeches fell down, bleeding continued for about two more hours. The site of the bites was wrapped in a pressure bandage thereafter. Two hours later the patients left the hospital with the instruction of physical rest at home, removal of the pressure bandage and tapes the next day. The patients returned on days 3, 7 and 21 after treatment for follow-up examinations. Leeches were used only once and then deposited.
Comparator Since it is impossible to prevent leeches from biting once they are in contact with the skin, a true placebo for a leech therapy seemed hard to define. Therefore, a comparator with least possible impact was chosen as control intervention. As a general condition, this procedure was also to be applied once, to be able to give some sensation to the patient, and not to sustain effects for the clinical condition. Transcutaneous electrical nerve stimulation (TENS), if applied only once, was considered to fulfill these conditions.10 The electrodes of a 2-channel-apparatus (model sm-2, schwa-medico, Germany) were placed in pairs above and below of the joint cavity, thus giving transversal currents in the joint. TENS therapy was given at 50 cycles/s for 10 min with an intensity at threshold, which means patients could barely register the current. After therapy, they left the center and returned for visits on days 3, 7, and 21 without further TENS therapy, which might thus be considered to act as a sham therapy
Design, main outcome parameters and statistics This is a randomised controlled clinical trial in a crossover design. Patients were block-randomised by a computer generated list with a block length of four into one of the two treatment groups (group 1 started with leeching, while group 2 started with TENS). Randomisation was done by a biostatistician (U.M.) and kept in coded sealed envelopes, one for each patient, which were opened after individual written consent was given. Cross-over took place 6 weeks after the first treatment. With another 3 weeks of observation, total study period was 9 weeks. Main outcome parameters were Lequesne’s index (L.I.), a dimensionless combined score for pain and function, and overall assessment of complaints by a visual analog scale (VAS, 0 to 10 cm). L.I. has been used in many studies with osteoarthritis, esp. with NSAID as main outcome parameter.11,12 Secondary parameters were physicians’ as well as patients’ assessments of satisfaction with therapy on days 21 and 63 on a 5-point Likert-type scale (very satisfied, satisfied, undecided, dissatisfied, very dissatisfied), and safety. Due to insufficient data on clinical effect size at that time, an exact calculation of sample size was not possible. A rough estimate was based on experience in the center with inpatients after a maximum observational period of 14 days, during which reductions of L.I. by from initial means of appr. 12.0 + 2.5 by appr. 2.5 units had been observed, thus leading to 43 patients, assuming a power of 0.9 and a level of significance ˛ = 0.05. Rapid fading of beneficial effects thereafter
Randomised controlled trial with medical leeches for osteoarthritis of the knee
•
Randomised patients N = 52
• •
Group 1 (leeches first) N= 25
• • • •
Non-randomised patients N = 20 At least one exlusion criterium present (N = 9) At least one inclusion criterium not present (N = 8) Unwillingness to randomisation (N=3)
Group 2 (TENS first) N = 25
Drop-outs (N = 5) Non-compliance (N = 2) Consent revoked without explanation (N = 1) Undisclosure of exclusion criterium (N = 1) Exacerbation after strain (N=1)
Finished per protocol N = 22
Figure 1
3
• • •
Drop-outs (N = 7) Non-compliance (N = 4) Intercurrent infection (N = 2) New anti-coagulation before leeches (N = 1)
Finished per protocol N = 18
CONSORT flow diagram of study patients.
was assumed. We aimed at a minimum of 50 patients to be enrolled. The statistical analysis followed the principle presented in the literature,13 extended from a standard one measurement per period approach to a situation with repeated measurements per treatment period. The chosen ANOVA approach allowed the detection of a carry-over effect in terms of a sequence by treatment interaction. The estimate of the period specific treatment effect was adjusted for time by using linear and quadratic contrasts for days 0, 3, 7, 21 and again 42, 45, 49, and 63. In case of a carry-over effect, the strategy of analysis was determined to discard the measurements of the second periods and perform a standard parallel group comparison using the Mann—Whitney-U-test (MWU) at each time point after the start of intervention by looking at individual changes as compared to baseline. Bonferroni’s adjustment for the overall alpha error was used to establish a possible treatment effect on the global p-level 0.05. Categorical values were described using frequencies. Metric data was summarized by descriptive statistics as means, standard deviations, etc. For comparison between groups as to anamnestic and demographical data, the Mann—Whitney-U-test (MWU) was used. All tests performed were two-sided. Groups were compared with a chi square test.
Results Patients 52 patients were randomised into the two groups (intent to treat ITT, also see Fig. 1: 41 women, 11 men, mean age 68.3 ± 10.2 years; group 1: 27 patients; group 2: 25 patients). 40 completed the study per protocol (group 1:
22 patients; group 2: 18 patients). Of the 12 patients who did not finish the study, 6 were non-compliant and did not show up at differing visits without explanation (2 group 1, 4 group 2). The remaining 6 had to be withdrawn for different reasons: 2 (group 2) had interfering infections preventing them from visits on time, 1 (group 2), had to start anti-coagulation before crossover, which was a criterium of exclusion, 1 (group1) explicitly withdrew his permission without any explanation, and 1 (group1) had initially disclosed a criterium of exclusion and thus had to be excluded later, while 1 (group1) experienced exacerbation of symptoms (see below).
Main outcome parameters At baseline, the two groups did not show any significant differences with regard to anthropometric and anamnestic data as well as main outcome parameters L.I. and VAS (p > 0.05, chi-square test). In group 1, mean values for L.I. decreased significantly from day 0 to day 21 (see Table 1). At day 42, we still found a significant (p < 0.0019) difference in favour of leeching. We thus observed a significant phase effect for this main outcome parameter and had to limit evaluation to the first period before crossover (days 0—21) in the sense of a twoarmed randomised controlled trial. Thus, the second part of the study including possible long-term effects can only be interpreted as observational data. In group 2 we only observed a slight but insignificant decrease for VAS between days 0 and 3. At day 42, there still was no significant change compared to baseline. Observational data: decrease in L.I. for group 1 remained almost unchanged even until the end of the study (see Fig. 2). TENS (sham) treatment after crossover did not show relevant changes on L.I. (no further testing).
4
R. Stange et al. Table 1
Main outcome parameters (mean ± 1 standard deviation, *p < 0.001 double-sided Mann—Whitney-U-test). Day 0
Day 3
Day 7
Day 21
Group 1
L.I. VAS [cm]
12.07 ± 4.24 5.89 ± 2.40
9.17 ± 4.80 4.55 ± 2.60
9.2 ± 4.66 4.30 ± 2.65
9.37 ± 5.10 4.16 ± 2.67
Group 2
L.I. VAS [cm]
11.66 ± 3.42 5.63 ± 2.35
10.88 ± 3.56 5.09 ± 2.18
11.27 ± 3.56 5.36 ± 2.31
11.63 ± 3.05 5.61 ± 2.61
Figure 2 Lequesne’s index over the study period of 63 days, separated into phase 1 (independent groups, days 0—21, given also as differences to day 0) and phase 2 (after crossover, days 42—63) [box—whisker-plots: bar within box: median, box: two quartiles, whiskers: outliers: circles >1.5 box heights, asterisk >2.5 box heights] Intent to treat analysis, leeches n = 27 with initial leeches therapy, TENS n = 25 with initial TENS therapy. Significant difference between LI0 and LI21 for leeches therapy (2p < 0.001, WILCOXON test for related samples).
Randomised controlled trial with medical leeches for osteoarthritis of the knee
5
Figure 3 Overall assessment of complaints (VAS 0—10) over the whole study period of 63 days. Separation into phase 1 (independent groups, days 0—21, given also as differences to day 0) and phase 2 (after cross-over, days 42—63) [box—whisker-plots: bar within box: median, box: two quartiles, whiskers: outliers: circles >1.5 box heights, asterisk >2.5 box heights]. Intent to treat analysis, leeches n = 27 with initial leech therapy, TENS n = 25 with initial TENS therapy. Significant difference between LI0 and LI21 for leech therapy (2p < 0.001, WILCOXON test for related samples).
Lequesne’s index dropped by similar amounts when leeching was done as second procedure in group 2: 2.3 units 3 days after leech therapy (day 45). This reduction remained almost unchanged until the end of the study (day 63). Again, there was a significant difference between the two treatment groups at days 3, 7, and 21 with respect to ‘‘change to baseline’’ (MWU: p = 0.007, p = 0.004, p < 0.001). Similar results were observed for overall assessment of complaints VAS (Fig. 3): during the first phase, mean values in group 1 decreased from baseline 5.9 cm to 4.3 at day 3 by 1.6 cm (27.1%), resp. to 4.2 by 1.7 cm (28.8%) at day 21 (2p < 0.001, double-sided Mann—Whitney-U-test). In group 2 TENS therapy was not followed by any significant
improvement: slight decrease from 5.6 cm to 5.1 at day 3 by 0.5 cm (8.9%), followed again by a complete rebound to baseline 5.6 cm at day 21.
Secondary outcome parameter Combined judgment ‘very satisfied’ and ‘satisfied’ for effect for leeches was judged superior as compared to TENS by physicians (82% group 1, resp. 50% group 2 for leeches vs. 9%, resp. 18% for TENS), whereas physicians’ judgment was clearly inferior as compared to patients’ except for leeching in group 1 (see Fig. 4).
6
Figure 4 Patients’ and physicians’ satisfaction 21 days after each therapy (given as % for sum of judgments ‘very satisfied’ and ‘satisfied’ from a 5-point Likert-type scale).
Adverse effects During the study one adverse event (AE) occurred affecting the osteoarthritis. One patient (group 1) terminated the study untimely after acute exacerbation of his osteoarthritis, probably due to too much physical stress on the joint. The event was judged as to have no causal relation to the study treatment. There were no other unwanted side effects, except reversible local irritations of mild intensity.
Discussion Primary outcome To our knowledge, this was the first randomised controlled clinical trial with medicinal leeches at the time of planning, published as abstract before.14 Osteoarthritis of the knee in stadium II according to Jaeger and Wirth was chosen due to incidence, clinical impact and prior observation of clinical benefit after leech therapy. As expected, the comparator, a single TENS treatment, did not show significant long- or short-term effects, and therefore seemed to act as a sham therapy. One single therapy with leeches showed a significant reduction in both main outcome parameters, Lequesne’s index and total complaints (VAS) in both groups. Therapeutic benefit stayed with only slight disimprovement over at least 9 weeks. If individual changes to baseline are considered, we observed a significant difference stable over the first treatment period of 21 days between both groups. Due to phase effects, confirmatory evaluation had to be restricted to that period, which however did not affect significance of differences at any time until day 21. Maximum reduction of L.I. was 2.7 units and of VAS 2.1 cm after leeches, about 30% less than the maximum of 3.5 units that we were able to observe in both arms of another randomised controlled clinical trial, where we treated patients in one arm with 150 mg/d of retarded diclofenac over 4 weeks, while the others received another complementary treatment.15 In that trial, patient criteria and ways of recruition were quite similar as here. Results may thus be comparable. 150 mg/d of retarded diclofenac
R. Stange et al. is a highly efficient therapy, not well tolerated on the long run. In a non-randomised pilot study, Michalsen et al. compared leeches with physical therapy in 10 patients with osteoarthritis of the knee.16,17 Only four leeches instead of eight here were used in a single application and 4 weeks observation. Mean reduction of VAS (0—10) was 3.9 units, which is nearly twice as measured in this study. This difference in effect size may be due to different criteria of inclusion, as a classification for osteoarthritis is not mentioned, and to the smaller number of patients. Furthermore, there could have been more expectation bias due to the non-randomised study design and VAS as sole outcome parameter might be more exposed to suggestive effects. The same group later did a randomised controlled trial with 51 patients and topical diclofenac as control therapy, showing basically a similar course of outcome measured by the Western Ontario and McMaster Universities Osteoarthritis Index WOMAC.18 Meanwhile, further randomised clinical trials with leeches for osteoarthritis of the first carpometacarpal joint have been published also by Michalsen et al.19 and of the knee by Andereya et al..20 The latter reported basically similar effect sizes as the prior randomised controlled trial,18 both reporting the WOMAC score. For the first time, however, Andereya et al. used a sham procedure for leeches. All patients had inhibition of vision during therapy. After short needle pricks as a sham intervention, identical wound dressing was applied. At the end, patients were asked about blinding, which was not successful. It seems questionable whether successful blinding can be achieved in leech trials, esp. as patients must be given information about a possible slight itching and visible traces of bites for about 1 week. Also, Andereya et al. randomised half of verum patients to undergo another leech therapy 1 week after the first, after which they reported even further improvement.
Secondary outcome After TENS, there was a discrepancy in both groups between patients’ better overall satisfaction by secondary in contrast to almost unchanged primary outcome, which may reflect high expectation bias. Physicians clearly assessed leeching more favourable than did patients when done initially in group 1 (Fig. 4). We do not have an explanation for this. Less satisfaction on the side of physicians compared to patients for the remaining three situations (Fig. 4) seems to be a feature in most clinical trials.
Safety Slight itching as local reaction to the bites appears to be inevitable, but is mild and needs no further medical assistance. We did not observe any contact eczema, as has been described at least in one case after use of a hirudine containing cream,21 nor other allergic reactions to the macromolecules in the leech saliva. However, we lack information on those 7 patients (13.5% of those enrolled) who discontinued the study, 3 of whom had had leeches before.
Randomised controlled trial with medical leeches for osteoarthritis of the knee
Limitations Shortcomes of this study are the small number of patients, the length of the observational period, the unblinded design, the lack of images like MRI of the knees before and after treatment, and the absence of biopsies for further analysis. Thus, we were not able to make a contribution to fundamental effects of leeches when biting humans. In their secretion, quite a number of substances have been identified, like egline, hemetine, caline, orgelase, hyaluronidase, and hirudine. Especially the latter one has received sufficient pharmacological investigation. It has strong fibrinolytic properties, thus being able to explain for drainage of blood and interstitial fluid in the surrounding of bites. Dwellines, another group of substances in their saliva, have anti-inflammatory effects. It remains to be shown by further research, whether the tiny amounts of absorbed excretions can account for local or even systemic effects.
Conclusions Thus, leeching may to be able to exert an effect size close to that of a conventional therapy with NSAID. One advantage could be the low frequency and severity of side effects, as compared to the use of NSAID with its well-known potential of mucosal damage and its clinical consequences, which have been estimated in recent years.22,23 Serious complications occur especially with older people and during long-term use, as is often necessary in the treatment of osteoarthritis. Due to little clinical research on leeches published at the time of planning the trial, the design of the study had to follow along prior experiences, esp. with regards to the number of leeches to be used and the length of the expected effect. In a recent monograph, Mueller summarizes the work of different authors, part of which is recommending repeated leech therapy in intervals shorter than our study length to enhance the effect.7 In summary, leeching significantly improves pain and functional symptoms of patients with osteoarthritis of the knee (stadium II) compared to a sham therapy over at least 9 weeks. The size of the clinical effect as demonstrated in this study is of clinical relevance whit an excellent safety profile. Due to the statistical significance of the clinical effects, more clinical studies should be performed to optimize the therapy, compare it with standard therapies, and get more knowledge about mechanisms of action.
Conflict of interest All authors declare that they have no conflict of interest within the subject under publication.
7
References 1. Crater KC. Leechcraft in nineteenth century British medicine. J R Soc Med 2001;94:38—42. 2. Heunio J. De Hirudinum—–usu et efficacia in Medicinia. Greifswald: Universitaet Greifswald; 1652. 3. Eccles SJ, Butler PE. Leechcraft. J R Soc Med 2001;94:204. 4. Cole D. Clinical hirudology: revival of an ancient art. N Z Med J 1985;98:28—9. 5. Sinclair-Loutit KW. Leechcraft. J R Soc Med 2001;94:2259. 6. Oostheer P. Leeching. S Afr Med J 1970;44:678. 7. Mueller IW. Handbuch der Blutegeltherapie, 1st ed. Heidelberg: Haug Verlag; 2000. 8. Shah S. Why leeches influence my physical examination. Lancet 1998;352(9145):2015—115. 9. Jaeger M, Wirth CJ. Praxis der Orthopädie. Stuttgart: Thieme Verlag; 1986. 10. Melzack R, Wall PD. Pain mechanisms: a new theory. Life Sci 1976;19:1757—62. 11. Lequesne M, et al. Incidence of severity for osteoarthritis of the hip and knee: value in comparison with other assessments tests. Scand J Rheum 1987;18 Suppl:85—9. 12. Lequesne M. Klinische und roentgenologische Verlaufsbeobachtungen bei Hüft- und Kniegelenksarthrosen—–Methoden und Ergebnisse. Zeitsch Rheumatol 1994;53:243—9. 13. Stephen Senn. Cross-over trials in clinical research. Chirchester: Wiley; 1993. 14. Stange R, Moser C, Uehleke B, Buehring M. Randomised controlled trial with leeches in patients with gonarthrosis. Altern Ther Health Med 2001;7:31. 15. Stange R, Moser C, Goedings P, Mansmann U, Buehring M. Randomised trial with mistletoe injections for osteoarthritis of the knee in comparison to treatment with diclofenac. FoKoMed 2000;7:117—8. 16. Michalsen A, Moebus S, Deuse U, Esch T, Dobos G. Leech therapy in knee osteoarthritis. Altern Ther Health Med 2001;7:25. 17. Michalsen A, Deuse U, Esch T, Dobos G, Moebus S. Effect of leeches therapy (Hirudo medicinalis) in painful osteoarthritis of the knee: a pilot study. Ann Rheum Dis 2001;60:986. 18. Michalsen A, Klotz S, Luedtke R, Moebus S, Spahn G, Dobos GJ. Effectiveness of leech therapy in osteoarthritis of the knee: a randomised, controlled trial. Ann Intern Med 2003;139(9):724—30. 19. Michalsen A, Luedtke R, Cesur O, Afra D, Musial F, Baecker M, et al. Effectiveness of leech therapy in women with symptomatic arthrosis of the first carpometacarpal joint: a randomized controlled trial. Pain 2008;137(2):452—9. 20. Andereya S, Stanzel S, Maus U, Mueller-Rath R, Mumme T, Siebert CH, et al. Assessment of leech therapy for knee osteoarthritis: a randomized study. Acta Orthop 2008;79(2):235—43. 21. Blaise S, Le Brun V, Sparsa A, Delrous JL, Bonnetblanc JM. Contact dermatitis with Hirudo medicinalis. Ann Dermatol Venereol 2002;129(12):1380—2. 22. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279:1200—5. 23. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of non-steroridal anti-inflammatory drugs. N Engl J Med 1999;340:1888—99.
Available online at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/ctim
Randomised controlled trial with medical leeches for osteoarthritis of the knee Rainer Stange a,∗, Claudia Moser a, W. Hopfenmueller b, U. Mansmann c, M. Buehring a, B. Uehleke a a
Charité - Universitaetsmedizin Berlin - Campus Benjamin Franklin, Department for Natural Medicine, Koenigstr. 63, D-14109 Berlin, Germany b Charité - Universitaetsmedizin Berlin, Institute for Biometry and Clinical Epidemiology, Hindenburgdamm 30, D-12203 Berlin, Germany c Ludwig-Maximilian-University Munich, Institute for Medical Data Processing, Biometry und Epidemiology, Germany Available online 15 November 2011
KEYWORDS Randomised controlled trial; Complementary medicine; Leeches; Leeching; Hirudinea; Hirudo medicinalis; Osteoarthritis of the knee; Lequesne’s index; VAS
∗
Summary Objectives: To evaluate the possible efficacy of medical leeches (Hirudo medicinalis) in the treatment of patients with active osteoarthritis of the knee. Design: Unblinded, randomised controlled trial with outpatients in a crossover design with single interventions of either leeches or transcutaneous electrical nerve stimulation (TENS) as comparator. Main outcome measures: Change in Lequesne’s combined index for pain and function and change (L.I.) and overall assessment of complaints by visual analog scale (VAS). Cross-over at day 42, with further observation period of 21 days. Results: 52 out of 72 screened patients were randomised (intent to treat) to initial treatment with either eight leeches (group 1: 27 patients) or TENS (group 2: 25 patients). Due to phase effects, confirmatory evaluation had to be restricted to the first period. Between days 0 and 21, we observed highly significant (p < 0.001) improvements for means of Lequesne’s index from 12.07 to 9.37 and for VAS from 5.89 to 4.16 cm for leeches, but no significant differences for TENS. Effect size as group difference was -2.50 for L.I. (95% confidence interval −3.88 to −1.11), resp. −1.86 cm for VAS (95% confidence interval −2.85 to −0.87 cm). 12 patients (5 group1, 7 group 2) did not finish the trial, mostly due to non-compliance (6). No serious adverse effects were observed. Conclusions: Single leech therapy showed significant, relevant and sustaining effects, comparable to other trials with leeches. The method deserves further research, esp. into mechanisms of possible specific effects and optimization of dosing by number of leeches and possible repeats. © 2011 Elsevier Ltd. All rights reserved.
Corresponding author. Tel.: +49 3080505 690; fax: +49 30 80505 692. E-mail addresses: [email protected], [email protected] (R. Stange).
0965-2299/$ — see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctim.2011.10.006
2
Introduction Over several thousand years, different medical cultures have been making use of treatment with leeches.1,2 In the 17th and 18th centuries, this treatment was widespread, and there seemed to be no limits as to frequency, topic extent, and number of leeches used. Even though leeching and other so-called humoral therapies were very popular and got established as a regime in naturopathy in different countries, balanced clinical assessments and controlled clinical studies are still missing.3—6 Today there is a striking disproportion between frequency of application and clinical documentation as it is well-known from other therapies. Despite intensive data retrieval (esp. Medline; keywords: leeches, leech, leech therapy, bloodletting, Hirudinea, and Hirudo officinalis) and inquiries at the manufactures and users of medicinal leeches, it was at the time of planning this study not possible to find any accurate planned clinical study or surveillance study except one7 and a rather anecdotal report.8 Next to varicosis, osteoarthritis is one of the most frequent and clinically remarkable indications for leeching. We conducted a randomised clinical study to investigate the therapeutical significance of a single treatment with medicinal leeches in patients with uncomplicated active osteoarthritis of the knee using validated measuring instruments.
Materials and methods Patients Patients with osteoarthritis of one or both knees with stadium II according to the classification of Jaeger and Wirth were included.9 With both-sided osteoarthritis, patients could be included, if a clear difference between sides could be found, in which case only the more affected knee was treated. Main exclusion criteria were undetermined complaints of both knees, chronic inflammatory diseases like rheumatoid arthritis, anemia (hemoglobin less than 12.0 g/dl for men, resp. 10.0 g/dl for women), malign and consumptive diseases, and regular intake of anticoagulant drugs as well as low dose acetylicsalicylic acid. The patients were asked for voluntary participation, and written consent was requested. The study was approved by the ethics committee of the Freie Universitaet Berlin, Germany.
Leeches and treatment The medicinal leeches were imported from a Turkish cultivation by a German import company (Moser Blutegelhandel, Fellbach, Germany). After arrival, leeches were kept in daily changed tap water for at least 48 h (minimum volume 1 l/leech) before application. Therapy consisted of a single application of eight medicinal leeches. Sites for bites were above and below the patella as well as medially and laterally in projection to the joint cavity. There was no preparation of the skin. As it is not always possible to let leeches bite, a minimum of six and a maximum of eight bites per treatment was considered to be a per protocol therapy. This minimum was achieved in all randomised patients. After biting, the
R. Stange et al. leeches were left as long as possible in their original position while knees were immobilized. When leeches fell down, bleeding continued for about two more hours. The site of the bites was wrapped in a pressure bandage thereafter. Two hours later the patients left the hospital with the instruction of physical rest at home, removal of the pressure bandage and tapes the next day. The patients returned on days 3, 7 and 21 after treatment for follow-up examinations. Leeches were used only once and then deposited.
Comparator Since it is impossible to prevent leeches from biting once they are in contact with the skin, a true placebo for a leech therapy seemed hard to define. Therefore, a comparator with least possible impact was chosen as control intervention. As a general condition, this procedure was also to be applied once, to be able to give some sensation to the patient, and not to sustain effects for the clinical condition. Transcutaneous electrical nerve stimulation (TENS), if applied only once, was considered to fulfill these conditions.10 The electrodes of a 2-channel-apparatus (model sm-2, schwa-medico, Germany) were placed in pairs above and below of the joint cavity, thus giving transversal currents in the joint. TENS therapy was given at 50 cycles/s for 10 min with an intensity at threshold, which means patients could barely register the current. After therapy, they left the center and returned for visits on days 3, 7, and 21 without further TENS therapy, which might thus be considered to act as a sham therapy
Design, main outcome parameters and statistics This is a randomised controlled clinical trial in a crossover design. Patients were block-randomised by a computer generated list with a block length of four into one of the two treatment groups (group 1 started with leeching, while group 2 started with TENS). Randomisation was done by a biostatistician (U.M.) and kept in coded sealed envelopes, one for each patient, which were opened after individual written consent was given. Cross-over took place 6 weeks after the first treatment. With another 3 weeks of observation, total study period was 9 weeks. Main outcome parameters were Lequesne’s index (L.I.), a dimensionless combined score for pain and function, and overall assessment of complaints by a visual analog scale (VAS, 0 to 10 cm). L.I. has been used in many studies with osteoarthritis, esp. with NSAID as main outcome parameter.11,12 Secondary parameters were physicians’ as well as patients’ assessments of satisfaction with therapy on days 21 and 63 on a 5-point Likert-type scale (very satisfied, satisfied, undecided, dissatisfied, very dissatisfied), and safety. Due to insufficient data on clinical effect size at that time, an exact calculation of sample size was not possible. A rough estimate was based on experience in the center with inpatients after a maximum observational period of 14 days, during which reductions of L.I. by from initial means of appr. 12.0 + 2.5 by appr. 2.5 units had been observed, thus leading to 43 patients, assuming a power of 0.9 and a level of significance ˛ = 0.05. Rapid fading of beneficial effects thereafter
Randomised controlled trial with medical leeches for osteoarthritis of the knee
•
Randomised patients N = 52
• •
Group 1 (leeches first) N= 25
• • • •
Non-randomised patients N = 20 At least one exlusion criterium present (N = 9) At least one inclusion criterium not present (N = 8) Unwillingness to randomisation (N=3)
Group 2 (TENS first) N = 25
Drop-outs (N = 5) Non-compliance (N = 2) Consent revoked without explanation (N = 1) Undisclosure of exclusion criterium (N = 1) Exacerbation after strain (N=1)
Finished per protocol N = 22
Figure 1
3
• • •
Drop-outs (N = 7) Non-compliance (N = 4) Intercurrent infection (N = 2) New anti-coagulation before leeches (N = 1)
Finished per protocol N = 18
CONSORT flow diagram of study patients.
was assumed. We aimed at a minimum of 50 patients to be enrolled. The statistical analysis followed the principle presented in the literature,13 extended from a standard one measurement per period approach to a situation with repeated measurements per treatment period. The chosen ANOVA approach allowed the detection of a carry-over effect in terms of a sequence by treatment interaction. The estimate of the period specific treatment effect was adjusted for time by using linear and quadratic contrasts for days 0, 3, 7, 21 and again 42, 45, 49, and 63. In case of a carry-over effect, the strategy of analysis was determined to discard the measurements of the second periods and perform a standard parallel group comparison using the Mann—Whitney-U-test (MWU) at each time point after the start of intervention by looking at individual changes as compared to baseline. Bonferroni’s adjustment for the overall alpha error was used to establish a possible treatment effect on the global p-level 0.05. Categorical values were described using frequencies. Metric data was summarized by descriptive statistics as means, standard deviations, etc. For comparison between groups as to anamnestic and demographical data, the Mann—Whitney-U-test (MWU) was used. All tests performed were two-sided. Groups were compared with a chi square test.
Results Patients 52 patients were randomised into the two groups (intent to treat ITT, also see Fig. 1: 41 women, 11 men, mean age 68.3 ± 10.2 years; group 1: 27 patients; group 2: 25 patients). 40 completed the study per protocol (group 1:
22 patients; group 2: 18 patients). Of the 12 patients who did not finish the study, 6 were non-compliant and did not show up at differing visits without explanation (2 group 1, 4 group 2). The remaining 6 had to be withdrawn for different reasons: 2 (group 2) had interfering infections preventing them from visits on time, 1 (group 2), had to start anti-coagulation before crossover, which was a criterium of exclusion, 1 (group1) explicitly withdrew his permission without any explanation, and 1 (group1) had initially disclosed a criterium of exclusion and thus had to be excluded later, while 1 (group1) experienced exacerbation of symptoms (see below).
Main outcome parameters At baseline, the two groups did not show any significant differences with regard to anthropometric and anamnestic data as well as main outcome parameters L.I. and VAS (p > 0.05, chi-square test). In group 1, mean values for L.I. decreased significantly from day 0 to day 21 (see Table 1). At day 42, we still found a significant (p < 0.0019) difference in favour of leeching. We thus observed a significant phase effect for this main outcome parameter and had to limit evaluation to the first period before crossover (days 0—21) in the sense of a twoarmed randomised controlled trial. Thus, the second part of the study including possible long-term effects can only be interpreted as observational data. In group 2 we only observed a slight but insignificant decrease for VAS between days 0 and 3. At day 42, there still was no significant change compared to baseline. Observational data: decrease in L.I. for group 1 remained almost unchanged even until the end of the study (see Fig. 2). TENS (sham) treatment after crossover did not show relevant changes on L.I. (no further testing).
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R. Stange et al. Table 1
Main outcome parameters (mean ± 1 standard deviation, *p < 0.001 double-sided Mann—Whitney-U-test). Day 0
Day 3
Day 7
Day 21
Group 1
L.I. VAS [cm]
12.07 ± 4.24 5.89 ± 2.40
9.17 ± 4.80 4.55 ± 2.60
9.2 ± 4.66 4.30 ± 2.65
9.37 ± 5.10 4.16 ± 2.67
Group 2
L.I. VAS [cm]
11.66 ± 3.42 5.63 ± 2.35
10.88 ± 3.56 5.09 ± 2.18
11.27 ± 3.56 5.36 ± 2.31
11.63 ± 3.05 5.61 ± 2.61
Figure 2 Lequesne’s index over the study period of 63 days, separated into phase 1 (independent groups, days 0—21, given also as differences to day 0) and phase 2 (after crossover, days 42—63) [box—whisker-plots: bar within box: median, box: two quartiles, whiskers: outliers: circles >1.5 box heights, asterisk >2.5 box heights] Intent to treat analysis, leeches n = 27 with initial leeches therapy, TENS n = 25 with initial TENS therapy. Significant difference between LI0 and LI21 for leeches therapy (2p < 0.001, WILCOXON test for related samples).
Randomised controlled trial with medical leeches for osteoarthritis of the knee
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Figure 3 Overall assessment of complaints (VAS 0—10) over the whole study period of 63 days. Separation into phase 1 (independent groups, days 0—21, given also as differences to day 0) and phase 2 (after cross-over, days 42—63) [box—whisker-plots: bar within box: median, box: two quartiles, whiskers: outliers: circles >1.5 box heights, asterisk >2.5 box heights]. Intent to treat analysis, leeches n = 27 with initial leech therapy, TENS n = 25 with initial TENS therapy. Significant difference between LI0 and LI21 for leech therapy (2p < 0.001, WILCOXON test for related samples).
Lequesne’s index dropped by similar amounts when leeching was done as second procedure in group 2: 2.3 units 3 days after leech therapy (day 45). This reduction remained almost unchanged until the end of the study (day 63). Again, there was a significant difference between the two treatment groups at days 3, 7, and 21 with respect to ‘‘change to baseline’’ (MWU: p = 0.007, p = 0.004, p < 0.001). Similar results were observed for overall assessment of complaints VAS (Fig. 3): during the first phase, mean values in group 1 decreased from baseline 5.9 cm to 4.3 at day 3 by 1.6 cm (27.1%), resp. to 4.2 by 1.7 cm (28.8%) at day 21 (2p < 0.001, double-sided Mann—Whitney-U-test). In group 2 TENS therapy was not followed by any significant
improvement: slight decrease from 5.6 cm to 5.1 at day 3 by 0.5 cm (8.9%), followed again by a complete rebound to baseline 5.6 cm at day 21.
Secondary outcome parameter Combined judgment ‘very satisfied’ and ‘satisfied’ for effect for leeches was judged superior as compared to TENS by physicians (82% group 1, resp. 50% group 2 for leeches vs. 9%, resp. 18% for TENS), whereas physicians’ judgment was clearly inferior as compared to patients’ except for leeching in group 1 (see Fig. 4).
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Figure 4 Patients’ and physicians’ satisfaction 21 days after each therapy (given as % for sum of judgments ‘very satisfied’ and ‘satisfied’ from a 5-point Likert-type scale).
Adverse effects During the study one adverse event (AE) occurred affecting the osteoarthritis. One patient (group 1) terminated the study untimely after acute exacerbation of his osteoarthritis, probably due to too much physical stress on the joint. The event was judged as to have no causal relation to the study treatment. There were no other unwanted side effects, except reversible local irritations of mild intensity.
Discussion Primary outcome To our knowledge, this was the first randomised controlled clinical trial with medicinal leeches at the time of planning, published as abstract before.14 Osteoarthritis of the knee in stadium II according to Jaeger and Wirth was chosen due to incidence, clinical impact and prior observation of clinical benefit after leech therapy. As expected, the comparator, a single TENS treatment, did not show significant long- or short-term effects, and therefore seemed to act as a sham therapy. One single therapy with leeches showed a significant reduction in both main outcome parameters, Lequesne’s index and total complaints (VAS) in both groups. Therapeutic benefit stayed with only slight disimprovement over at least 9 weeks. If individual changes to baseline are considered, we observed a significant difference stable over the first treatment period of 21 days between both groups. Due to phase effects, confirmatory evaluation had to be restricted to that period, which however did not affect significance of differences at any time until day 21. Maximum reduction of L.I. was 2.7 units and of VAS 2.1 cm after leeches, about 30% less than the maximum of 3.5 units that we were able to observe in both arms of another randomised controlled clinical trial, where we treated patients in one arm with 150 mg/d of retarded diclofenac over 4 weeks, while the others received another complementary treatment.15 In that trial, patient criteria and ways of recruition were quite similar as here. Results may thus be comparable. 150 mg/d of retarded diclofenac
R. Stange et al. is a highly efficient therapy, not well tolerated on the long run. In a non-randomised pilot study, Michalsen et al. compared leeches with physical therapy in 10 patients with osteoarthritis of the knee.16,17 Only four leeches instead of eight here were used in a single application and 4 weeks observation. Mean reduction of VAS (0—10) was 3.9 units, which is nearly twice as measured in this study. This difference in effect size may be due to different criteria of inclusion, as a classification for osteoarthritis is not mentioned, and to the smaller number of patients. Furthermore, there could have been more expectation bias due to the non-randomised study design and VAS as sole outcome parameter might be more exposed to suggestive effects. The same group later did a randomised controlled trial with 51 patients and topical diclofenac as control therapy, showing basically a similar course of outcome measured by the Western Ontario and McMaster Universities Osteoarthritis Index WOMAC.18 Meanwhile, further randomised clinical trials with leeches for osteoarthritis of the first carpometacarpal joint have been published also by Michalsen et al.19 and of the knee by Andereya et al..20 The latter reported basically similar effect sizes as the prior randomised controlled trial,18 both reporting the WOMAC score. For the first time, however, Andereya et al. used a sham procedure for leeches. All patients had inhibition of vision during therapy. After short needle pricks as a sham intervention, identical wound dressing was applied. At the end, patients were asked about blinding, which was not successful. It seems questionable whether successful blinding can be achieved in leech trials, esp. as patients must be given information about a possible slight itching and visible traces of bites for about 1 week. Also, Andereya et al. randomised half of verum patients to undergo another leech therapy 1 week after the first, after which they reported even further improvement.
Secondary outcome After TENS, there was a discrepancy in both groups between patients’ better overall satisfaction by secondary in contrast to almost unchanged primary outcome, which may reflect high expectation bias. Physicians clearly assessed leeching more favourable than did patients when done initially in group 1 (Fig. 4). We do not have an explanation for this. Less satisfaction on the side of physicians compared to patients for the remaining three situations (Fig. 4) seems to be a feature in most clinical trials.
Safety Slight itching as local reaction to the bites appears to be inevitable, but is mild and needs no further medical assistance. We did not observe any contact eczema, as has been described at least in one case after use of a hirudine containing cream,21 nor other allergic reactions to the macromolecules in the leech saliva. However, we lack information on those 7 patients (13.5% of those enrolled) who discontinued the study, 3 of whom had had leeches before.
Randomised controlled trial with medical leeches for osteoarthritis of the knee
Limitations Shortcomes of this study are the small number of patients, the length of the observational period, the unblinded design, the lack of images like MRI of the knees before and after treatment, and the absence of biopsies for further analysis. Thus, we were not able to make a contribution to fundamental effects of leeches when biting humans. In their secretion, quite a number of substances have been identified, like egline, hemetine, caline, orgelase, hyaluronidase, and hirudine. Especially the latter one has received sufficient pharmacological investigation. It has strong fibrinolytic properties, thus being able to explain for drainage of blood and interstitial fluid in the surrounding of bites. Dwellines, another group of substances in their saliva, have anti-inflammatory effects. It remains to be shown by further research, whether the tiny amounts of absorbed excretions can account for local or even systemic effects.
Conclusions Thus, leeching may to be able to exert an effect size close to that of a conventional therapy with NSAID. One advantage could be the low frequency and severity of side effects, as compared to the use of NSAID with its well-known potential of mucosal damage and its clinical consequences, which have been estimated in recent years.22,23 Serious complications occur especially with older people and during long-term use, as is often necessary in the treatment of osteoarthritis. Due to little clinical research on leeches published at the time of planning the trial, the design of the study had to follow along prior experiences, esp. with regards to the number of leeches to be used and the length of the expected effect. In a recent monograph, Mueller summarizes the work of different authors, part of which is recommending repeated leech therapy in intervals shorter than our study length to enhance the effect.7 In summary, leeching significantly improves pain and functional symptoms of patients with osteoarthritis of the knee (stadium II) compared to a sham therapy over at least 9 weeks. The size of the clinical effect as demonstrated in this study is of clinical relevance whit an excellent safety profile. Due to the statistical significance of the clinical effects, more clinical studies should be performed to optimize the therapy, compare it with standard therapies, and get more knowledge about mechanisms of action.
Conflict of interest All authors declare that they have no conflict of interest within the subject under publication.
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References 1. Crater KC. Leechcraft in nineteenth century British medicine. J R Soc Med 2001;94:38—42. 2. Heunio J. De Hirudinum—–usu et efficacia in Medicinia. Greifswald: Universitaet Greifswald; 1652. 3. Eccles SJ, Butler PE. Leechcraft. J R Soc Med 2001;94:204. 4. Cole D. Clinical hirudology: revival of an ancient art. N Z Med J 1985;98:28—9. 5. Sinclair-Loutit KW. Leechcraft. J R Soc Med 2001;94:2259. 6. Oostheer P. Leeching. S Afr Med J 1970;44:678. 7. Mueller IW. Handbuch der Blutegeltherapie, 1st ed. Heidelberg: Haug Verlag; 2000. 8. Shah S. Why leeches influence my physical examination. Lancet 1998;352(9145):2015—115. 9. Jaeger M, Wirth CJ. Praxis der Orthopädie. Stuttgart: Thieme Verlag; 1986. 10. Melzack R, Wall PD. Pain mechanisms: a new theory. Life Sci 1976;19:1757—62. 11. Lequesne M, et al. Incidence of severity for osteoarthritis of the hip and knee: value in comparison with other assessments tests. Scand J Rheum 1987;18 Suppl:85—9. 12. Lequesne M. Klinische und roentgenologische Verlaufsbeobachtungen bei Hüft- und Kniegelenksarthrosen—–Methoden und Ergebnisse. Zeitsch Rheumatol 1994;53:243—9. 13. Stephen Senn. Cross-over trials in clinical research. Chirchester: Wiley; 1993. 14. Stange R, Moser C, Uehleke B, Buehring M. Randomised controlled trial with leeches in patients with gonarthrosis. Altern Ther Health Med 2001;7:31. 15. Stange R, Moser C, Goedings P, Mansmann U, Buehring M. Randomised trial with mistletoe injections for osteoarthritis of the knee in comparison to treatment with diclofenac. FoKoMed 2000;7:117—8. 16. Michalsen A, Moebus S, Deuse U, Esch T, Dobos G. Leech therapy in knee osteoarthritis. Altern Ther Health Med 2001;7:25. 17. Michalsen A, Deuse U, Esch T, Dobos G, Moebus S. Effect of leeches therapy (Hirudo medicinalis) in painful osteoarthritis of the knee: a pilot study. Ann Rheum Dis 2001;60:986. 18. Michalsen A, Klotz S, Luedtke R, Moebus S, Spahn G, Dobos GJ. Effectiveness of leech therapy in osteoarthritis of the knee: a randomised, controlled trial. Ann Intern Med 2003;139(9):724—30. 19. Michalsen A, Luedtke R, Cesur O, Afra D, Musial F, Baecker M, et al. Effectiveness of leech therapy in women with symptomatic arthrosis of the first carpometacarpal joint: a randomized controlled trial. Pain 2008;137(2):452—9. 20. Andereya S, Stanzel S, Maus U, Mueller-Rath R, Mumme T, Siebert CH, et al. Assessment of leech therapy for knee osteoarthritis: a randomized study. Acta Orthop 2008;79(2):235—43. 21. Blaise S, Le Brun V, Sparsa A, Delrous JL, Bonnetblanc JM. Contact dermatitis with Hirudo medicinalis. Ann Dermatol Venereol 2002;129(12):1380—2. 22. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279:1200—5. 23. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of non-steroridal anti-inflammatory drugs. N Engl J Med 1999;340:1888—99.