DÄ internationalArchive47/2018The Effectiveness of Leech Therapy in Chronic Low Back Pain

Original article

The Effectiveness of Leech Therapy in Chronic Low Back Pain

A randomized controlled trial

Dtsch Arztebl Int 2018; 115(47): 785-92; DOI: 10.3238/arztebl.2018.0785

Hohmann, C; Stange, R; Steckhan, N; Robens, S; Ostermann, T; Paetow, A; Michalsen, A

Background: Leech therapy has been found to be effective in the treatment of a number of chronic musculoskeletal pain syndromes. Leeches are also often used empirically to treat chronic low back pain, but data from clinical trials have been lacking to date. We therefore conducted the first randomized trial of leech therapy for chronic low back pain.

Methods: Patients with chronic low back pain were randomized to receive either a single session of local treatment with 4–7 leeches or four weekly sessions of exercise therapy (1 hour each) led by a physical therapist. The primary endpoint was a change in average back pain intensity, as measured using a 100-mm visual analog scale (VAS), after 28 days. Secondary endpoints included functional impairment (Roland–Morris Disability Questionnaire, Hannover Functional Ability Questionnaire), quality of life (Short-Form Health Questionnaire [SF 36]), pain perception (pain perception scale = Schmerzempfindungsskala [SES]), depressivity (Center for Epidemiological Studies Depression Scale [CES-D]), and analgesic consumption (questionnaire/diary). Trial visits took place before treatment and on days 28 ± 3 and 56 ± 5 after the start of treatment; the overall duration of the trial was 56 ± 5 days.

Results: The mean low back pain score improved from 61.2 ± 15.6 before treatment to 33.1 ± 22.4 on day 28 in the leech therapy group (n = 25) and from 61.6 ± 14.8 to 59.8 ± 16.7 in the exercise therapy group (n = 19) (group difference −25.2; 95% confidence interval [−41.0; −9.45]; p = 0.0018). Significant benefits of leech therapy were also found at both time points with respect to physical impairment and function as well as physical quality of life. The patients’ expectations from treatment were higher in the leech therapy group but did not significantly affect the findings.

Conclusion: A single session of leech therapy is more effective over the short term in lowering the intensity of pain over the short term and in improving physical function and quality of life over the intermediate term (4 weeks and 8 weeks, respectively). The limitations of this trial are the lack of blinding and the small number of patients. Leech therapy appears to be an effective treatment for chronic low back pain.

LNSLNS

Chronic low back pain is a complex health problem of considerable epidemiological and therapeutic importance. It is one of the seven most commonly occurring diseases worldwide (1). In most cases the pain is caused by the interaction of several factors. Lack of exercise, overweight, overexertion, and a number of psychosomatic factors can all play a part and often reinforce each other in a vicious circle leading to chronification among the very large numbers of patients with acute low back pain (25). Despite advances in treatment—achieved largely by means of multimodal activation programs as recommended by current guidelines (6)—the success of treatment in individual cases leaves much to be desired, with increasing chronification and escalating therapy.

Leech therapy is a traditional medical procedure that is frequently employed for the treatment of chronic pain syndromes in European, Arabian, and Asian naturopathy. Historically, there is a long tradition of using leeches for clinical purposes, all the way from ancient Egypt and medieval Europe (7) to the recent renaissance in leech therapy (8). The leeches used in modern medical practice are mostly imported from Turkey and Bulgaria. Germany currently has one single leech breeding facility operating according to the standards of good manufacturing practice (GMP).

A number of randomized controlled trials have demonstrated the efficacy of leech therapy in alleviating pain and improving function for patients with osteoarthritis of the knee, osteoarthritis of the carpometacarpal joint of the thumb, and epicondylitis (9, 10). A meta-analysis has supported the effectiveness of leech therapy in osteoarthritis of the knee (11). Although back pain is by no means fully comparable with other musculoskeletal pain syndromes, on the basis of these findings it seems reasonable to investigate the efficacy of leech therapy for this indication.

The mechanism of action of leech therapy has not been fully elucidated. During the approximately 60 min of application the leeches release their saliva, containing more than 100 biologically active substances (12), into the wound. Recent biochemical studies have identified substances in the saliva that possess not only coagulation-inhibiting but also analgesic and anti-inflammatory properties (13). Furthermore, the leeches’ saliva contains hyaluronidase, which increases the penetration depth of the other active substances. It is thought that the overall clinical effect is complemented by an antinociceptive action of the leech bite and by nonspecific effects arising from the unusual nature of the treatment.

The aim of this clinical trial was to investigate the clinical effectiveness of leech therapy for chronic low back pain.

Methods

Study design

This proof-of-concept study was planned, approved, and conducted as a two-center, open, nonblinded, randomized controlled clinical trial. Formally a pharmaceutical trial, it was carried out according to the requirements of the German Medicines Act and the Ordinance on the Implementation of Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Use in Humans (GCP-V).

Eligible for inclusion were male and female patients between 18 and 70 years of age with confirmed, previously diagnosed chronic low back pain (chronic nonspecific lumbar spine syndrome). Patients were excluded on grounds of medicinal anticoagulation treatment, anemia, and for other reasons (see eMethods for details).

For the purposes of this trial four to seven leeches could be applied on one single occasion in an area 3 to 15 cm from the spinal column at the level of vertebrae L1 to S3. The control treatment comprised one 60-min session of exercise therapy each week for 4 weeks.

The outcome measures were determined at baseline, after 28 ± 3 days (visit 1; ± 3 corresponds to the tolerance set a priori for the time of measurement), and after 56 ± 5 days (visit 2). The primary outcome measure was the absolute change in average back pain intensity during the previous week (as measured using a 100-mm visual analog scale [VAS]) at the 28-day follow-up. The secondary outcome measures were, among others:

  • The intensity/frequency of analgesic medication, as recorded by the patient in a diary
  • Limitations on daily functioning imposed by back pain (measured using the Roland–Morris Disability Questionnaire [RMDQ] and the Hannover Functional Ability Questionnaire for measuring back pain–related disability [Funktionsfragebogen Hannover für Rückenschmerzen, FFbH-R]) (14, 15)
  • General quality of life (measured using the Short-Form Health Survey 36 [SF-36]) (16)
  • Mood (using the Center for Epidemiological Studies Depression Scale [CES-D]) (17)
  • Perception of pain (using the Pain Perception Scale [Schmerzempfindungsskala, SES]) (18).

Consumption of analgesics as medication on demand

To avoid any bias arising from changes of medication, no specific medication was stipulated for use in emergencies. To achieve approximate comparability for an important parameter in the treatment of chronic pain, the daily maximum dose as stated in the product information was multiplied by 28 to yield a monthly maximum dose. In the trial, the intakes of individual analgesics were summarized for the 4-week period immediately preceding baseline and the probands kept diaries to record consumption in the first (V1) and second (V2) 4-week periods after baseline. These intakes are presented here as percentages of the monthly maximum dose. The calculated monthly maximum doses for the drugs used were: metamizole (Novaminsulfon) 112 000 mg/month (4000 mg/day), diclofenac 4200 mg/month (150 mg/day), paracetamol 112 000 mg/month (4000 mg/day), ibuprofen 67 200 mg/month (2400 mg/day), acetylsalicylic acid 84 000 mg/month (3000 mg/day), naproxen 35 000 mg/month (1250 mg/day).

A detailed description of the methods employed can be found in the eMethods.

Results

A total of 103 participants were contacted. Thirty-four of them either did not meet the inclusion criteria or exhibited insufficient interest in the trial. The remaining 69 participants were examined by the study physician and 17 could not be included. Eight participants who left the trial after randomization but before the first data acquisition point were replaced (Figure 1). Before the commencement of treatment, expectations were higher among the members of the leech therapy group than in the control group. However, ANCOVA (Analysis of Covariance) of the primary outcome measure revealed that the participants’ expectations had no significant influence on the result (mean difference 3.11; 95% confidence interval [−12.1; 5.9]; p = 0.4969). This was also the case for all of the secondary outcome measures.

Figure 1

The mean pain intensity was 61.2 ± 15.6 on the 100-mm VAS for the leech therapy group and 61.6 ± 14.7 for the exercise group. The average intake of analgesic medications, expressed as percentage of monthly maximum dose, was 6.40% versus 11.88% respectively (Table 1). Before the beginning of the study, in addition to pain medication (100%), the participants’ low back pain led to at least one session of physiotherapy in 100/91% of cases (intervention/control), massages in 82/73%, acupuncture in 53/91%, and rehabilitation measures in 53/45% (Table 2).

All members of the leech therapy group took part in the intervention. A median of seven leeches (min. five, max. seven) were used per treatment. The members of the back school group attended a median of four (min. three, max. four) of the four exercise sessions.

After inclusion of 44 participants the first intermediate evaluation was performed as foreseen by the sequential study design, and the trial was ended with a significant p value of 0.0018 for the primary outcome measure, a positive result (Table 3).

Primary result

The leech therapy group showed a significantly greater reduction in VAS-rated pain at day 28 than the control group (Figure 2, Table 3). At this time point, the VAS-assessed pain in the leech group had decreased by 25.2 mm more than that in the exercise group ([−41.0; −9.5]; p = 0.0018). Precise figures for all parameters, both in the per-protocol analysis without imputation of missing values and in the intention-to-treat evaluation with imputation can be found in eTables 1 and 2.

Figure 2

Secondary results

The VAS (for global impairment), the function inventories (RMDQ, FFbH-R), the SES, and the SF-36 all showed significant superiority of leech therapy on day 28 (Table 1, Figure 3).

Figure 3

On day 56, leech therapy remained significantly superior for the function inventories RMDQ and FFbH-R and for physical quality of life. The difference between the two groups was no longer statistically significant for VAS-assessed pain (p = 0.056). The mean absolute pain reduction was still significantly improved in the leech group, but the values were scattered more widely.

The mood-related mental health scales of SF-36 and the SES showed improvement in both groups (study effect). The difference between the groups was not significant.

Safety and tolerability

Altogether, 20 adverse events were documented in 20 participants, none of them serious. Five of these events were classified as definitely connected with the leech therapy (prolonged continuation of bleeding up to 24 h [without anemia], n = 3; more intense itching on more than 3 days, n = 2). Six events (increased back pain) were classed as probably related to the treatment, five of them in the exercise group and one in the leech group. In this latter case there was a temporal association with heavy physical exertion on the day before the visit. Five events were rated as unlikely to be connected with the treatment, three in the leech group (influenza-like illness, cystitis, suspected biliary colic) and two in the back school group (migraine, influenza-like illness). Two members of the physiotherapy group dropped out because of worsening back pain.

Consumption of analgesics as medication on demand

The intake of analgesics decreased significantly in the leech therapy group, from 6.40% of the monthly maximum dose at baseline to 2.35% at V1 and 1.94% at V2. Analgesic consumption in the control group followed a U curve, from 11.88% at baseline to 8.83% at V1 and 10.63% at V2. The groups were heterogeneous, in that two members of the control group were taking very large amounts of analgesic medications at baseline.

Discussion

This randomized clinical trial was the first to evaluate the effectiveness of leech therapy in the management of nonspecific low back pain and compare it with a guideline-based standard treatment, i.e., kinesitherapy and back exercises. The reduction in pain at 28 days was significantly greater in the leech therapy group, and both functional improvement and enhancement of physical quality of life were more pronounced in the leech group at 28 days and 56 days. The outcome of exercise treatment was less positive than expected, possibly due to the fact that in many cases it was commenced at an early stage.

Both the almost 50% improvement in absolute pain and the absolute group difference of >20 mm on the VAS point to a clinically meaningful effect of leech therapy. The pain reduction achieved with leeches is quantitatively equivalent to the effects of conventional pharmacological treatments, e.g., nonsteroidal antirheumatic drugs. Hedges g, a measure of effect size, was −1.30 at V1 and −1.06 at V2. In other words, the effect size was strong (>0.8) at both follow-up visits. The corresponding figures for RMDQ functional improvement were −0.95 at V1 and −1.56 at V2. (See eTable 3 for a detailed presentation of these results.)

eTable 3

Other, nonmedicinal procedures recommended in current international guidelines (19), such as physiotherapy, acupuncture, the Alexander technique, or yoga, are less effective than documented for leech therapy in our trial (20). Leech therapy should therefore be considered a useful option for the nonmedicinal/noninvasive management of back pain.

Limitations

One major limitation of this trial is the lack of blinding to treatment. The characteristic leech therapy process, with application of living creatures to the skin, the initial bite, and the subsequent prolonged bleeding, makes effective blinding practically impossible. Indeed, the attempt at blinding in one of the knee osteoarthritis studies was unsuccessful, with most patients correctly identifying their treatment (21). The absence of blinding means that the size of the nonspecific (placebo) effect cannot be measured accurately. However, statistical allowance for the probands’ expectations—an important factor for nonspecific treatment effects—also showed no essential influence on the results.

Nevertheless, it has to be assumed that the overall effect includes a considerable nonspecific component. Experimental clinical studies of nonpharmacological procedures in the treatment of pain show that the size of the treatment effect increases both with the invasiveness of the intervention and with the intensity of care (22). Leech therapy is characterized by a certain degree of invasiveness (leech bite, prolonged bleeding) and by a striking treatment setting (complex, unusual intervention involving living creatures). A strong nonspecific effect is thus likely due to the resulting neurocognitive processes.

The lack of a parameter based on objective assessment, e.g., the Physician’s Global Assessment Scale, is another limiting factor. The fact that 91% of the members of the back school group had previously received comparable measures can also be viewed as a limitation. However, repeated use of physiotherapy is recommended in the guidelines.

A further limitation is the low number of cases in the trial. However, this was based on correct calculation and early attainment of the discontinuation criterion in the sequential design and was correspondingly determined by the high effect size of the leech therapy. The high drop-out rate in the control group, resulting in an imbalance of 25:19 evaluable participants on intention-to-treat criteria, must also be considered a limiting factor. However, a model calculation of the effect sizes for a hypothetical balanced distribution of 22:22 showed no meaningful alteration of the results, so we do not believe that the difference in group size essentially weakens the conclusions.

The groups differed with regard to analgesic intake at baseline. This may be viewed as showing a difference in perception of pain, particularly in view of the fact that analgesic consumption declined sharply in the treatment group. One last limitation is the possible selection bias, given that the participants were recruited in a tertiary study center.

Possible mechanisms of action

Several different mechanisms of action may have contributed to the clinical amelioration of back pain by the leech therapy. In osteoarthritis, the effect has been attributed particularly to the analgesic/anti-inflammatory substances present in leech saliva. However, an anti-inflammatory action seems less likely to be relevant for chronic nonspecific back pain than for symptomatic osteoarthritis. A positive effect of leech therapy has also been described in other clinical contexts, even including an individual case of cancer pain relief (23). The leech bite, in analogy with other invasive procedures such as injections and acupuncture, can be expected to have an antinociceptive action. Regional blood and lymph loss with resulting decongestion and improvement of the microcirculation may have a relaxing effect on the musculature. Finally, the above-mentioned nonspecific (placebo-like) actions may contribute to the overall effect.

Safety

In this trial, as in earlier studies of the use of leech therapy for pain relief, there were no clinically meaningful adverse events. Cases of infection with the symbiont Aeromonas hydrophila, found in leech saliva, have been repeatedly reported from plastic and reconstructive surgery (24), but this has not yet been observed in pain therapy. However, patients should be informed about the high rate of occurrence of localized itching and the persistence of localized reddening of the skin for a period of up to several weeks, as observed in this study.

Duration of effect

Our data permit no conclusions as to the duration of effect of leech therapy in patients with nonspecific low back pain. For osteoarthritis, mean durations of effect of 4 to 8 months have been reported (25). In principle, leech therapy can be repeated when the effect wears off; in our experience, second and subsequent treatments are just as effective as the first. In individual cases, however, there is the risk of the patient becoming allergic to components of leech saliva, precluding long-term treatment.

Summary

This first randomized controlled trial demonstrates the effectiveness of leech therapy for chronic nonspecific low back pain. Larger randomized and observational studies are needed to investigate the reproducibility of the effects, the adverse effects, and acceptance among less selected cohorts of patients. Furthermore, the comparative effectiveness and the long-term effects should be evaluated in further clinical, preferably multicenter, trials. In the event that the results are positive, coverage of the costs of leech therapy not only by private medical insurance, as at present in Germany, but also by statutory insurance should be discussed.

Following previous studies, this trial provides further clear evidence that leech therapy probably represents an effective means of ameliorating chronic regional pain syndromes in the musculoskeletal apparatus as a whole. It may be worthwhile to try combining the pronounced relief of symptoms achieved by leech therapy with activating treatments.

Acknowledgments

The authors are grateful to the Karl and Veronika Carstens Foundation and the Biebertal Leech Farm for partial financial support and to Evelyn Hoff for coordination and supervision of the trial at the Study Center, KPW Garbsen.

Conflict of interest statement

Mr. Hohmann receives fees for regular lectures at leech therapy training courses in cooperation with Biebertal Leech Farm GmbH. He has received reimbursement of travel and accommodation costs in connection with the training of therapists in leech treatment techniques.

Prof. Michalsen has received study support (third-party funding) from the Biebertal Leech Farm. Biebertal Leech Farm GmbH supported the trial materially (provision of leeches) and by paying the official study fees, the costs of insuring the probands, and, in part, the personnel costs for a 2-month period (study physician).

The remaining authors declare that no conflict of interests exists.

Data sharing

The authors are willing to share the data arising from this study with others, for scientific purposes.

Manuscript submitted on 3 January 2018, revised version accepted on
20 July 2018

Translated from the original German by David Roseveare

Corresponding author
Prof. Dr. med. Andreas Michalsen
Klinik für Innere Medizin, Abteilung für Naturheilkunde
Immanuel Krankenhaus
Königstr. 63,
14109 Berlin, Germany
a.michalsen@immanuel.de

Supplementary material

eMethods, eTables:
www.aerzteblatt-international.de/18m0785

1.
Murray CJL, Lopez AD: Measuring the global burden of disease. N Engl J Med 2013; 369: 448–57 CrossRef MEDLINE
2.
Shemory ST, Pfefferle KJ, Gradisar IM: Modifiable risk factors in patients with low back pain. Orthopedics 2016; 39: e413–6 CrossRef MEDLINE
3.
Bundes­ärzte­kammer, Kassenärztliche Bundesvereinigung, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften: Nationale VersorgungsLeitlinie Nicht-spezifischer Kreuzschmerz – Langfassung, 2. Auflage. Version 1, 2017 .
4.
Clauw DJ: Diagnosing and treating chronic musculoskeletal pain based on the underlying mechanism(s). Best Pract Res Clin Rheumatol 2015; 29: 6–19 CrossRef MEDLINE
5.
Casser HR, Seddigh S, Rauschmann M: Acute lumbar back pain— investigation, differential diagnosis and treatment. Dtsch Arztebl Int 2016; 113: 223–34 CrossRef
6.
Chenot JF, Greitemann B, Kladny B, Petzke F, Pfingsten M, Schorr SG: Clinical practice guideline: non-specific low back pain. Dtsch Arztebl Int 2017; 114: 883–90 VOLLTEXT
7.
Whitaker IS, Rao J, Izadi D, Butler PE: Historical article: Hirudo medicinalis: ancient origins of, and trends in the use of medicinal leeches throughout history. Br J Oral Maxillofac Surg 2004; 42: 133–7 CrossRef
8.
Koeppen D, Aurich M, Rampp T: Medicinal leech therapy in pain syndromes: a narrative review. Wien Med Wochenschr 2013; 164: 95–102 CrossRef MEDLINE
9.
Bäcker M, Lüdtke R, Afra D, et al.: Effectiveness of leech therapy in chronic lateral epicondylitis: a randomized controlled trial. Clin J Pain 2011; 27: 442–7 CrossRef MEDLINE
10.
Michalsen A, Lüdtke R, Cesur O, et al.: Effectiveness of leech therapy in women with symptomatic arthrosis of the first carpometacarpal joint: a randomized controlled trial. Pain 2008; 137: 452–59 CrossRef MEDLINE
11.
Lauche R, Cramer H, Langhorst J, Dobos G: A systematic review and meta-analysis of medical leech therapy for osteoarthritis of the knee. Clin J Pain 2014; 30: 63–72 CrossRef MEDLINE
12.
Baskova IP, Zavalova LL, Basanova AV, Moshkovskii SA, Zgoda VG: Protein profiling of the medicinal leech salivary gland secretion by proteomic analytical methods. Biochemistry (Mosc) 2004; 69: 770–5 CrossRef
13.
Hildebrandt JP, Lemke S: Small bite, large impact-saliva and salivary molecules in the medicinal leech, Hirudo medicinalis. Naturwissenschaften 2011; 98: 995–1008 CrossRef MEDLINE
14.
Exner V, Keel P: Measuring disability of patients with low-back pain—validation of a German version of the Roland & Morris disability questionnaire. Schmerz 2000; 14: 392–400 CrossRef MEDLINE
15.
Klasen BW, Hallner D, Schaub C, Willburger R, Hasenbring M: Validation and reliability of the German version of the Chronic Pain Grade questionnaire in primary care back pain patients. Psychosoc Med 2004; 1: Doc07 MEDLINE PubMed Central
16.
Bullinger M: German translation and psychometric testing of the SF-36 Health Survey: Preliminary results from the IQOLA project. Soc Sci Med 1995; 41: 1359–66 CrossRef
17.
Gerbershagen HU, Kohlmann T: Die deutsche Fassung der „Center for Epidemiologic Studies Depression Scale (CES-D)“. Übersetzung und psychometrische Validierung. Lübeck/Mainz 2000.
18.
Geissner E: Die Schmerz-Empfindungs-Skala (SES). Göttingen: Hogrefe 1996 MEDLINE
19.
Qaseem A, Wilt TJ, McLean RM, Forciea MA, Clinical Guidelines Committee of the American College of Physicians: Noninvasive treatments for acute, subacute, and chronic low back pain: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2017; 166: 514–30 CrossRef MEDLINE
20.
Wieland LS, Skoetz N, Pilkington K, Vempati R, D’Adamo CR, Berman BM: Yoga treatment for chronic non-specific low back pain. Cochrane Database Syst Rev. 2017 Jan 12; 1: CD010671 CrossRef
21.
Andereya S, Stanzel S, Maus U, et al.: Assessment of leech therapy for knee osteoarthritis: a randomized study. Acta Orthop 2008; 79: 235–43 CrossRef MEDLINE
22.
Jensen KB, Kaptchuk TJ, Kirsch I, et al.: Nonconscious activation of placebo and nocebo pain responses. Proc Natl Acad Sci US A 2012; 109: 15959–64 CrossRef MEDLINE PubMed Central
23.
Kalender ME, Comez G, Sevinc A, Dirier A, Camci C: Leech therapy for symptomatic relief of cancer pain. Pain Med 2010; 11: 443–5 CrossRef MEDLINE
24.
Whitaker IS, Oboumarzouk O, Rozen WM, et al.: The efficacy of medicinal leeches in plastic and reconstructive surgery: a systematic review of 277 reported clinical cases. Microsurgery 2012; 32: 240–50 CrossRef MEDLINE
25.
Michalsen A, Roth M, Dobos G: Medicinal leech therapy. Stuttgart, New York: Thieme 2007 CrossRef
26.
O’Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 1979; 35: 549–56 CrossRef
27.
Wassmer G: Planning and analyzing adaptive group sequential survival trials. Biometrical J 2006; 48: 714–29 CrossRef
28.
Michalsen A, Klotz S, Lüdtke R, Moebus S, Spahn G, Dobos GJ: Effectiveness of leech therapy in osteoarthritis of the knee: a randomized, controlles trial. Ann Intern Med 2003; 139: 724–30 CrossRef
Charité – University Medicine Berlin, corporate member of the Free University Berlin, Humboldt University of Berlin, and Berlin Institute of Health, Institute of Social Medicine, Epidemiology and Health Economics, Foundation Chair of Clinical Naturopathy: Christoph-Daniel Hohmann, Dr. Rainer Stange, Dr. Nico Steckhan, Prof. Andreas Michalsen
Department of Internal Medicine, Division of Naturopathy, Immanuel Hospital Berlin: Christoph-Daniel Hohmann, Dr. Rainer Stange, Dr. Nico Steckhan, Prof. Andreas Michalsen
Department of Psychology, Faculty of Health, Witten/Herdecke University: Dipl.-Stat. Sibylle Robens, Prof. Ostermann
KPW Garbsen, Center for Physiotherapy: Dr. Paetow
1.Murray CJL, Lopez AD: Measuring the global burden of disease. N Engl J Med 2013; 369: 448–57 CrossRef MEDLINE
2.Shemory ST, Pfefferle KJ, Gradisar IM: Modifiable risk factors in patients with low back pain. Orthopedics 2016; 39: e413–6 CrossRef MEDLINE
3.Bundes­ärzte­kammer, Kassenärztliche Bundesvereinigung, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften: Nationale VersorgungsLeitlinie Nicht-spezifischer Kreuzschmerz – Langfassung, 2. Auflage. Version 1, 2017 .
4.Clauw DJ: Diagnosing and treating chronic musculoskeletal pain based on the underlying mechanism(s). Best Pract Res Clin Rheumatol 2015; 29: 6–19 CrossRef MEDLINE
5.Casser HR, Seddigh S, Rauschmann M: Acute lumbar back pain— investigation, differential diagnosis and treatment. Dtsch Arztebl Int 2016; 113: 223–34 CrossRef
6.Chenot JF, Greitemann B, Kladny B, Petzke F, Pfingsten M, Schorr SG: Clinical practice guideline: non-specific low back pain. Dtsch Arztebl Int 2017; 114: 883–90 VOLLTEXT
7. Whitaker IS, Rao J, Izadi D, Butler PE: Historical article: Hirudo medicinalis: ancient origins of, and trends in the use of medicinal leeches throughout history. Br J Oral Maxillofac Surg 2004; 42: 133–7 CrossRef
8.Koeppen D, Aurich M, Rampp T: Medicinal leech therapy in pain syndromes: a narrative review. Wien Med Wochenschr 2013; 164: 95–102 CrossRef MEDLINE
9.Bäcker M, Lüdtke R, Afra D, et al.: Effectiveness of leech therapy in chronic lateral epicondylitis: a randomized controlled trial. Clin J Pain 2011; 27: 442–7 CrossRef MEDLINE
10. Michalsen A, Lüdtke R, Cesur O, et al.: Effectiveness of leech therapy in women with symptomatic arthrosis of the first carpometacarpal joint: a randomized controlled trial. Pain 2008; 137: 452–59 CrossRef MEDLINE
11.Lauche R, Cramer H, Langhorst J, Dobos G: A systematic review and meta-analysis of medical leech therapy for osteoarthritis of the knee. Clin J Pain 2014; 30: 63–72 CrossRef MEDLINE
12.Baskova IP, Zavalova LL, Basanova AV, Moshkovskii SA, Zgoda VG: Protein profiling of the medicinal leech salivary gland secretion by proteomic analytical methods. Biochemistry (Mosc) 2004; 69: 770–5 CrossRef
13.Hildebrandt JP, Lemke S: Small bite, large impact-saliva and salivary molecules in the medicinal leech, Hirudo medicinalis. Naturwissenschaften 2011; 98: 995–1008 CrossRef MEDLINE
14.Exner V, Keel P: Measuring disability of patients with low-back pain—validation of a German version of the Roland & Morris disability questionnaire. Schmerz 2000; 14: 392–400 CrossRef MEDLINE
15.Klasen BW, Hallner D, Schaub C, Willburger R, Hasenbring M: Validation and reliability of the German version of the Chronic Pain Grade questionnaire in primary care back pain patients. Psychosoc Med 2004; 1: Doc07 MEDLINE PubMed Central
16.Bullinger M: German translation and psychometric testing of the SF-36 Health Survey: Preliminary results from the IQOLA project. Soc Sci Med 1995; 41: 1359–66 CrossRef
17.Gerbershagen HU, Kohlmann T: Die deutsche Fassung der „Center for Epidemiologic Studies Depression Scale (CES-D)“. Übersetzung und psychometrische Validierung. Lübeck/Mainz 2000.
18.Geissner E: Die Schmerz-Empfindungs-Skala (SES). Göttingen: Hogrefe 1996 MEDLINE
19.Qaseem A, Wilt TJ, McLean RM, Forciea MA, Clinical Guidelines Committee of the American College of Physicians: Noninvasive treatments for acute, subacute, and chronic low back pain: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2017; 166: 514–30 CrossRef MEDLINE
20.Wieland LS, Skoetz N, Pilkington K, Vempati R, D’Adamo CR, Berman BM: Yoga treatment for chronic non-specific low back pain. Cochrane Database Syst Rev. 2017 Jan 12; 1: CD010671 CrossRef
21.Andereya S, Stanzel S, Maus U, et al.: Assessment of leech therapy for knee osteoarthritis: a randomized study. Acta Orthop 2008; 79: 235–43 CrossRef MEDLINE
22.Jensen KB, Kaptchuk TJ, Kirsch I, et al.: Nonconscious activation of placebo and nocebo pain responses. Proc Natl Acad Sci US A 2012; 109: 15959–64 CrossRef MEDLINE PubMed Central
23.Kalender ME, Comez G, Sevinc A, Dirier A, Camci C: Leech therapy for symptomatic relief of cancer pain. Pain Med 2010; 11: 443–5 CrossRef MEDLINE
24.Whitaker IS, Oboumarzouk O, Rozen WM, et al.: The efficacy of medicinal leeches in plastic and reconstructive surgery: a systematic review of 277 reported clinical cases. Microsurgery 2012; 32: 240–50 CrossRef MEDLINE
25.Michalsen A, Roth M, Dobos G: Medicinal leech therapy. Stuttgart, New York: Thieme 2007 CrossRef
26.O’Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 1979; 35: 549–56 CrossRef
27.Wassmer G: Planning and analyzing adaptive group sequential survival trials. Biometrical J 2006; 48: 714–29 CrossRef
28.Michalsen A, Klotz S, Lüdtke R, Moebus S, Spahn G, Dobos GJ: Effectiveness of leech therapy in osteoarthritis of the knee: a randomized, controlles trial. Ann Intern Med 2003; 139: 724–30 CrossRef