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Minimal immunoreactive plasma β-endorphin and decrease of cortisol at standard analgesia or different acupuncture techniques

Harbach, H.*; Moll, B.; Boedeker, R.-H.; Vigelius-Rauch, U.*; Otto, H.*; Muehling, J.*; Hempelmann, G.*; Markart, P.

European Journal of Anaesthesiology: April 2007 - Volume 24 - Issue 4 - p 370–376
doi: 10.1017/S0265021506001906
Review
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Background and objective: Acupuncture has been claimed to be associated with activation of the endogenous antinociceptive system. The analgesic effects of acupuncture have been ascribed to β-endorphin interacting with opioid receptors. However, firstly, the release of β-endorphin into the blood has been proven to be induced by stress, i.e. under dysphoric conditions, and, secondly, if released under stress, β-endorphin has been shown not to be analgesic. Our aim was to test whether β-endorphin immunoreactive material is released into the cardiovascular compartment during acupuncture comparing the most frequently used types of acupuncture with standard pain treatment under apparently low stress conditions.

Methods: This prospective study included 15 male patients suffering from chronic low back pain. β-Endorphin immunoreactive material and cortisol were measured in the plasma of patients who underwent, in randomorder, therapy according to a standard pain treatment, traditional Chinese acupuncture, sham acupuncture, electro acupuncture and electro acupuncture at non-acupuncture points before, at and after the treatment. Statistical analysis was performed using two-way ANOVA with repeated measures.

Results: A decrease in plasma cortisol concentration measured over the five treatment protocols was highly significant (P < 0.001). The β-endorphin immunoreactive material concentrations in plasma were minimal at all times and in all treatment conditions. The influence of treatments by various acupuncture procedures on cortisol and β-endorphin immunoreactive material plasma concentrations over the three time points was not significantly different.

Conclusions: β-endorphin immunoreactive material in blood is not released by any type of acupuncture as tested under low stress conditions.

*University of Giessen, Department of Anaesthesiology, Intensive Care, Pain Therapy, Palliative Medicine, Germany

Justus-Liebig-University, Rudolf-Buchheim-Institute for Pharmacology, Germany

Justus-Liebig-University, Institute of Medical Statistics and Informatics, Germany

University of Giessen, Department of Internal Medicine, Medical Clinic II, Giessen, Germany

Correspondence to: Heinz Harbach, Department of Anaesthesiology, Intensive Care, Pain Therapy, Palliative Medicine, University of Giessen, Rudolf-Buchheim-Str. 7, D-35385 Giessen, Germany. E-mail: heinz.harbach@chiru.med.uni-giessen.de; ++49 641 9944401; Fax: ++49 641 9944409

Accepted for publication 18 September 2006

First published online 8 December 2006

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Introduction

Acupuncture is used to achieve analgesia in chronic and therapy-resistant pain syndromes. A recent meta- analysis demonstrated the positive influence of acupuncture in the treatment of chronic low back pain [1]. Many studies indicated that acupuncture activates a central antinociceptive system [2]. Endogenous ligands of opioid receptors are processed from pro-opiomelanocortin (POMC), proenkephalin and prodynorphin. β-Endorphin and met-enkephalin have the same amino acid sequence at their N-terminus, tyrosine-glycine-glycine-phenylalanine-methionine, that binds to opioid receptors. Therefore, analgesic properties are ascribed to these opioid peptides and especially β-endorphin, substances that are also regarded as mediators of the effects of non-pharmacological analgesic treatments such as acupuncture [3,4]. Accordingly, the results of one study showed increased β-endorphin serum concentrations after exercise in parallel with an altered pain perception [5]. However, a lack of interrelationship between exercise-induced alterations in pain perception and endorphin serum concentration was also demonstrated [6].

Clear evidence for a mechanism underlying the analgesic effect of acupuncture is still missing. There are reports on the involvement of β-endorphin, but these are controversial: an increase in β-endorphin plasma or serum concentrations is described just as often as no significant β-endorphin response in plasma (Table 1). With regard to these results, and without considering any additional information, β-endorphin cannot be made responsible for the analgesic effect of acupuncture. Detectable plasma β-endorphin levels under acupuncture might be explained as an acupuncture-induced stress response.

Table 1

Table 1

Differences in plasma β-endorphin levels might be due to the inconsistency in measuring β-endorphin. Frequently used assays measure β-endorphin-immunoreactive material (IRM), but do not differentiate between β-endorphin (1-31) and β-endorphin IRM. Although the cross-reactivity of assays with β-lipotropin was documented in some studies [3,4,7-14], this cross reactivity is ignored in many other studies [15-23].

Chronic back pain is a complex biological, psychical and social phenomenon [24]. Pain has lost its acute warning function in patients suffering from chronic back pain lasting longer than 3 months. Stress caused by behavioural impairment such as muscular hardening, emotional disability and social handicaps may be important for the origin and maintenance of chronic pain [25,26]. We were interested in studying the endocrinological stress reaction during acupuncture in patients suffering from chronic low back pain lasting longer than 6 months. Therefore, we tried to find out the impact of different acupuncture or alternative techniques at apparently low stress conditions on the release of β-endorphin IRM and cortisol. To investigate an endocrinological stress response under acupuncture, we determined β-endorphin IRM (t1/2: 20-40 min) [27,28] and cortisol (t1/2: 70-100 min) [29,30] as a long-term parameter of stress reaction. We measured β-endorphin IRM and cortisol in the plasma of patients receiving conventional pain treatment, traditional Chinese acupuncture (TCA), traditional Chinese acupuncture at non acupuncture points (NTCA) (sham acupuncture), electro acupuncture (EAP), and electro acupuncture at non-acupuncture (NEAP) points before, at and after the treatment.

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Methods

Patients

The study was approved by the University of Giessen Ethics Committee (Medical Faculty). Fifteen male patients (age: 43.4 ± 11.4 yr) were included in this randomized and observer blinded study. All patients suffered from chronic low back pain for more than 6 months. All patients were treated with oral Voltaren® (Novartis Pharma GmbH, Nuremberg, Germany) (diclofenac) 75 mg bd. Acute illness was excluded by medical investigations before inclusion into the study. In the majority of cases, pain treatment had been futile so far. Whole blood (30 mL) was taken from all participants at three time points during each of five treatments.

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Treatments

Patients were informed to receive five different treatments according to consensus recommendations for clinical trials of acupuncture [31]. Every patient was informed about a treatment sequence in random order. All treatments were described to the patients.

  1. Oral medication with diclofenac 2 × 75 mg twice daily (standard medication: MED).
  2. TCA:
    1. bladder meridian (Bl) - bladder - 23, 25, 40, 60
    2. ‘Lenkergefäss' (LG) - Du Mai - 3, 4
    3. kidney meridian (ki) - kidney - 3.
  3. NTCA = sham acupuncture 2 cm lateral to the acupuncture points as defined in point 2 [31,32].
  4. EAP; stimulation frequency 4-10 Hz at individually regulated current flow (Bl 25, 40).
  5. NEAP 2 cm lateral to the acupuncture points as defined in point 4; stimulation frequency 4-10 Hz at individually regulated current flow.

The acupuncture regimens were practised in terms of anatomic locations and documented at a standard nomenclature [33]. Randomization was achieved by allocating each patient to one of 120 possible treatment sequences using a sequence of random numbers from a computer-generated sequence (Excel 2000). Each treatment was applied once weekly between 1 p.m. and 3 p.m. The period between one treatment and the next was 1 week for every patient. Thus, every patient was under treatment for 5 weeks.

Acupuncture treatment was performed according to Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) recommendations [34]. For TCA we used 0.2 × 15 mm sterile silicon-coated steel needles (SEIRIN type B, 3B Scientific, Hamburg, Germany). We inserted the needle 0.5-1 cm into the subcutaneous tissue, until we elicited the ‘de qi' sensation. If necessary, the needle was introduced further, withdrawn slightly or rotated to achieve an adequate response. We treated seven points bilaterally; thus 14 needles were used. The needle retention time was 30 min after placement of the last acupuncture needle. There was no choice for auxiliary techniques or self-treatment by the patient as an adjunct to the acupuncture itself. The treatment was accomplished by a physician licensed in acupuncture by the German Society of Acupuncture (DÄGFA).

Finally, both groups of control interventions (NTCA and NEAP) were treated with the same methods as the TCA and EAP groups. The difference was that the needles were inserted 2 cm laterally to the defined acupuncture points.

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Plasma sample collection

With every type of treatment, blood (30 mL) was drawn from an antecubital vein at the following times (Figs 1 and 2):

Figure 1

Figure 1

Figure 2.

Figure 2.

Time 1 (tA): 15 min (00:15) after puncture of the antecubital vein (puncture: 00:00).

Time 2 (tB): 10 min after placement of the last acupuncture needle, or placement of electro acupuncture respectively (00:40).

Time 3 (tC): 5 min after displacement of the needles or end of electro acupuncture respectively (01:05).

At the times given above, 20 mL of blood was drawn into syringes containing sodium EDTA (0.08 g mL1) and an additional 10 mL into syringes without EDTA. These were immediately placed on ice and centrifuged at 1000 g (15 min at 4°C). Two 5-mL plasma aliquots from the supernatant were acidified with 1.0 N HCl (0.1 mL mL1 plasma), each to block enzymatic degradation of β-endorphin and its derivatives, immediately frozen and stored at −20°C until extraction. One serum aliquot was kept at 21°C until used for the determination of cortisol [35].

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Determination of βH-endorphin IRM (17-26)

βH-endorphin IRM (17-26) in the plasma extracts was determined in a one-site fluid-phase RIA as described in principle [36] and characterized [28]. Intra-assay and inter-assay coefficients of variation of the RIA were 3.1% and 5.3%, respectively. Cross reactivities with βH-endorphin (1-26), (1-27), (1-31) as well as N-acetyl-βH-endorphin (1-31) were 100%, the cross reactivity with βH-lipotropin was 50%, and cross reactivities with βH-endorphin (1-16) and (27-31) were below 0.1%; thus, the antibodies recognize fragment (17-26) of the βH-endorphin amino acid sequence. The detection limit varied between 2 and 6 pmol βH-endorphin (1-31) L1 plasma and was determined separately for each assay.

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Determination of cortisol

Cortisol was determined in plasma samples not subjected to acidification or extraction using a fluorescence polarization immunoassay (Immulite DPC, Los Angeles, CA, USA). Intra-assay and inter-assay coefficients of variation were 6.8-12.2% and 4.3-9.1%, and the detection limit was 2 μg L1 (5.5 nmol L1).

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Statistical analysis

Statistical evaluation of the data was planned as an exploratory data analysis. The effect of time and treatment on cortisol and β-endorphin IRM was tested by two-way ANOVA with repeated measures. Kolmogorov-Smirnov analysis demonstrated that plasma levels of β-endorphin and cortisol were normally distributed at time intervals tA, tB and tC. The results of the main effects and interaction of the two factors are presented in Table 2. SPSS for WINDOWS version 11.5 was used for data analysis.

Table 2

Table 2

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Results

The decrease in plasma cortisol concentration between time points tA and tB or tB and tC, respectively, as obtained for all five treatment protocols was highly significant (P < 0.001) (Table 2a,b; Fig. 1). Cortisol concentrations as measured at the three time points did not differ significantly between the five treatment groups.

A possible interaction between the treatment protocol and cortisol concentrations at times tA, tB and tC was also analysed. Although the decreases in concentration with time were highly significant, the concentrations proved independent of the different treatment protocols. Thus, there was no significant difference between the treatment methods with respect to the time points measured (Table 2b).

The β-endorphin IRM concentrations in plasma were low at all times under all treatment conditions (Table 2a, Fig. 2). We did not see any effect of any treatment on the β-endorphin IRM concentrations measured at times tA, tB and tC. A dependency between treatment and β-endorphin IRM concentration at times tA, tB and tC was tested. Again, there was no significant difference between the treatments with respect to the time point of measurement (Table 2b).

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Discussion

We have determined cortisol as a ‘long term parameter' of the endocrine response to stress. A highly significant decline in plasma cortisol concentration was seen for all treatment groups over the whole observation period. This indicates that acupuncture treatments were conducted under stress-reduced conditions and that the cortisol concentrations reflected reactions of the patients to stressors, which they had been exposed to before starting the treatment. A cortisol half-life of about 70 to 100 min is compatible with this observation.

In our previous studies, β-endorphin was measured under different stress conditions. In parallel with an increase in β-endorphin plasma concentrations during stress, an elevation in adrenocorticotropic hormone (ACTH) and cortisol plasma concentrations was observed [28,37] (for review, see also [38]). We also observed a significant correlation of pain severity with ACTH, β-LPH IRM and β-endorphin levels: postoperative pain severity increased with increasing β-endorphin plasma concentrations [39]. Under all investigated conditions, β-endorphin was released from the pituitary gland into the cardiovascular compartment as a stress responder and not as an analgesic.

Kho and colleagues measured a significant increase in β-endorphin levels during acupuncture and transcutaneous stimulation even before skin incision for abdominal surgery and also before laryngoscopy for intubation had been performed [23]. They interpreted this increase as a response to the electrical stimulation, which, despite anaesthesia, apparently represented a considerable stressor. This would be entirely compatible with our interpretation of β-endorphin release in terms of a stress response [40,41].

The endorphin IRM concentrations in the plasma were low under our treatment conditions and at all times. Following our interpretation of the significance of β-endorphin release, these β-endorphin concentrations in plasma are not compatible with any stress response to acupuncture. In agreement with our findings, no significant change or decrease in β-endorphin in plasma during acupuncture therapy was observed in several previous studies [7,8,18,21,23]. Our results are consistent with these studies as far as we observed low β-endorphin IRM concentrations in the plasma throughout the entire observation period and without any decline (Table 2b). Thus, our patients did not show symptoms of any type of acute stress. In addition, between the five treatments, no significant differences in β-endorphin concentrations were detected.

Plasma β-endorphin is still claimed to be responsible for analgesia under acupuncture conditions [42-48]. The rise of β-endorphin is discussed in all these studies as a reason for acupuncture analgesia. However, these authors disregard that this rise may not be due to acupuncture, but may reflect the response to any kind of stressor as for instance obesity treatment [43], respiratory burst [46], open heart surgery [47] or laser therapy for treatment of alcohol addiction [48].

Shortly after the discovery of the existence of endogenous opioids, the term ‘endorphins' (Eric Simon) was used for all endogenous opioids. Following the identification of the three precursors POMC, proenkephalin and prodynorphin the term ‘endorphins' was limited to the POMC-derived β-endorphin derivatives, including βH-endorphin (1-31). Therefore, scientific evidence for the role of ‘endorphins' in acupuncture analgesia may be based on measurements not only of β-endorphin but also of dynorphins or enkephalins. In fact, acupuncture-induced increases in the ‘endorphin levels' in serum, as reported by Stux and colleagues, proved to be increases in fraction one of dynorphin [49].

Another point is that certain patient groups, e.g. patients with neuropathic pain, may have very low levels of plasma β-endorphin [50]. One might consider that our patients also had a neuropathic pain profile, which might provide some explanation for the low plasma levels.

Finally, the hypothesis of β-endorphin-related analgesia of acupuncture is supported by studies using the opioid antagonist naloxone (see [49]). As early as 1983, however, Szczudlik and colleagues questioned the hypothesis of an acupuncture-induced release of β-endorphin from the pituitary gland into the cardiovascular compartment, since a significant elevation of plasma β-endorphin after acupuncture treatment could not be demonstrated [11]. Thus, the absence of a significant increase of plasma β-endorphin IRM under acupuncture treatment, as observed in these studies, further supports a negligible role for β-endorphin in acupuncture analgesia [20,21].

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                    Keywords:

                    ACUPUNCTURE; ACUPUNCTURE ANALGESIA; LOW BACK PAIN; STRESS; β-ENDORPHIN; CORTISOL

                    © 2007 European Society of Anaesthesiology