1 Department of Obstetrics and Gynaecology, Göteborg University, SE-413 45 Göteborg, 2 Fertility Centre Scandinavia, SE-402 29 Göteborg, 3 IVF centre Falun, SE-791 82 Falun and 4 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, SE-171 77 Stockholm, Sweden
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Abstract |
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Key words: acupuncture/evidence-based medicine/infertility safety/reproductive medicine
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Introduction |
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Evidence-based medicine (EBM) and acupuncture |
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Acupuncture is an example of a method of treatment that can be evidence-based if practitioners embrace standardization and conventional standard tools. The tools of evidence-based medicine (EBM) can help us to understand and explain the underlying mechanisms of the effects claimed for acupuncture. The practice of EBM means integrating individual expertise with the best available external clinical evidence from systematic research, and this clinically relevant research often comes from basic science (Sackett, 1997). We read the debate article with regret since the author did not appear to have taken the pains to read the documentation about the acupuncture mechanisms or articles referred to. As an example, Renckens (Renckens, 2002
) refers to a study in a category that uniformly reports favourable outcomes of electro-acupuncture (EA) (Chen, 1997
) and argues that conclusions were not drawn from a randomized clinical trial (RCT) of normal quality. This is correct since this study was conducted on ovariectomized rats (Chen, 1997
). The aim was to explain the mechanisms of EA in the regulation of the function of the hypothalamuspituitarygonadal (HPG) axis, which was related to effects of EA previously reported in women with polycystic ovarian syndrome (PCOS) by the same group (Chen and Yu, 1991
; Chen, 1997
).
We agree that the quality of clinical acupuncture studies is generally less than high and that properly designed and conducted RCTs in acupuncture are lacking. However, in recent years the effect of acupuncture on different conditions (pain and diseases) has been studied from a Western scientific perspective, and the results show that acupuncture has both a physiological and a psychological impact (Andersson and Lundeberg, 1995).
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RCT, experimental trials, and acupuncture |
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Attitudes to acupuncture and the psychological preparation before treatment are thought to influence the outcome. The power of the psycho-neuro-immunological effect of acupuncture could be very high in certain circumstances, and it is difficult to control these factors in the clinical situation. Kaptchuk discussed the importance of using a third no-treatment, no-placebo arm to differentiate between the perception of a placebo effect and the ordinary natural history of a condition (Kaptchuk, 1998).
The use of experimental trials, in both animals and humans, enables us to evaluate the effects and mechanisms of acupuncture in a structured manner. The use of anaesthesia in animal models is another way to exclude many environmental variables. The ideal way to establish acupuncture procedures that are effective would be to conduct controlled comparative studies that consider every relevant variable of treatment. Such studies have been informally reviewed (Ceccherelli et al., 2000). Moreover, if acupuncture can be established to be superior to placebo in some conditions, acupuncture might be considered to be credible. Placebo-controlled trials would then not be necessary for other similar conditions, and studies could then concentrate on direct comparisons with other treatment options. It seems sensible to aim at accumulating this type of trial in those clinical areas where trials already exist, and acupuncture appears to have a good effect size, such as in acute pain (Ernst and Pittler, 1998
). Whatever the methodological design chosen, it is crucial that it is adequately described to make it possible to interpret the outcomes, and if necessary, to repeat the trial.
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Is there a physiological basis for the use of acupuncture? |
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There is evidence that this hypothalamic ß-endorphin system has a central role in mediating the pain-relieving effect of acupuncture (Wang et al., 1990a,b
) as well as the changes seen in autonomic functions after acupuncture. The latter changes are probably caused by an inhibition of the vasomotor centre (VMC) (Andersson and Lundeberg, 1995
). This would result in a sustained decrease in general sympathetic tone with vasodilatation, increased skin temperature, and decreased blood pressure (Andersson and Lundeberg, 1995
).
ß-endorphin is also released into the blood from the hypothalamus via the anterior pituitary (Crine et al., 1978). This release is regulated by corticotrophin-releasing factor (CRF), which is produced and released from the paraventricular nucleus of the hypothalamus. CRF promotes the release of ß-endorphin, adrenocorticotrophic hormone (ACTH), and melanocyte-stimulating hormone in equimolar amounts through stimulation of the synthesis of their precursor, pro-opiomelanocortin. These hormones exert their effects in different target organs via the bloodstream.
Stress increases the activity of the hypothalamicpituitaryadrenal (HPA) axis and decreases reproductive functions. This suggests a close relationship between hormones of the HPA axis and those of the hypothalamicpituitarygonadal (HPG) axis. CRF, ACTH, ß-endorphin, and adrenal corticosteroids play an important role in modulating the effect of stress on reproductive functions (Rivier and Rivest, 1991). Via this route, acupuncture may exert an effect on both the HPA axis and the HPG axis. Acupuncture has been shown to alter plasma ß-endorphin levels and may thereby have an effect on the release of hypothalamic gonadotrophin-releasing hormone (GnRH) and pituitary gonadotrophin secretion (Chen and Yu 1991
; Stener-Victorin et al., 2000
, 2002
).
The two central ß-endorphinergic systems described above operate independently, but both can be stimulated by afferent nerve activity (i.e. manual acupuncture, EA, and muscle exercise) (Andersson and Lundeberg, 1995).
Another system that may be involved in the modulation of stress, pain, autonomic and immune functions is the oxytocinergic system. This system is activated by mild, non-painful, sensory stimulation such as 2-Hz EA, massage, vibration, and thermal stimulation (Uvnäs-Moberget al., 1993). Interestingly, oxytocin effects ß-endorphin release (Peterssonet al., 1996
). It is possible that oxytocin may account for some of the effects seen in rats that were given acupuncture including anxiolysis, increased pain withdrawal thresholds, and exploratory behaviour (Uvnäs-Moberget al., 1993
).
In extensive studies by Sato and collaborators, it has been shown that both mild, non-painful, and strong, painful, acupuncture stimulation modulate spinal reflexes (Sato et al., 1997). Strong, painful stimulation results in increased sympathetic tone and pain. Mild, non-painful stimulation has been shown to activate inhibitory systems in the spinal cord, resulting in segmental inhibition of sympathetic outflow (Sato et al., 1997
) and pain pathways, as predicted by the gate control theory (Melzack and Wall, 1965
).
It has been suggested that mild, non-painful stimulation of muscle afferents results in a decrease of glutamate and aspartate content in the dorsal horn, which may be mediated by a ß-amino-butyric acid ergic mechanism (Lundeberg, 1996). Sandkuehler has demonstrated a long-term depression of synaptic transmission in the dorsal horn by low-frequency stimulation of A
-fibres (Sandkuehler et al., 1997
). This depression of synaptic transmission was reduced or abolished by a blockage of N-methyl-D-aspartic acid receptors and may underlie segmental pain inhibition (Sandkuehler, 1996
).
This mechanism is strictly topographically related, and an optimal effect is obtained by stimulating the somatic segments related to the pain area and/or the innervation of the affected organ (Andersson and Lundeberg, 1995). It should be stressed that all of these modulating systems are under central control (Andersson and Lundeberg, 1995
; Sandkuehler 1996b; Sato et al., 1997
).
In the periphery, acupuncture exerts effects by antidromic nerve impulses. These antidromic impulses induce the release of substance P (SP), vasoactive intestinal polypeptide (VIP), and calcitonin gene-related peptide (CGRP), which are likely to result in vasodilatation and in increased nutrition from improved blood flow (Dawidson et al., 1998; Lundeberg et al., 1988
; Sato et al., 2000
).
It has been demonstrated that intense painful stimulation results in the activation of supraspinal pain inhibitory centres, and this mechanism is denoted diffuse noxious inhibitory controls (DNIC) or counter-irritation (Le Bars et al., 1979). The pain-modulating effect is related to the release of endogenous opioids (Willer et al., 1990
) and is not specific, nor is it related to the site of stimulation. DNIC is seen following the activation of nociceptive afferents, and the mechanism involves supraspinal pathways, with descending projections to the dorsal horn at every level. The effect of DNIC can be blocked by naloxone (Le Bars et al., 1992
). This system is probably involved in the mechanism of acupuncture analgesia, and the effect has been observed in both humans and animals (Le Bars et al., 1979
, 1992
). It is unlikely that DNIC is reinforced only by strong placebo, as stated by Renckens (Renckens, 2002
) who appears to have overlooked the physiological significance of the DNIC phenomena.
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Psychological impact of acupuncture |
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Reports from China have stressed the importance of psychologically preparing patients before surgery when acupuncture analgesia is to be used (Bonica, 1974). The purpose of this preparation was to increase the effectiveness of the procedure and possibly to enhance the magnitude of the analgesia. The importance of psychological factors before and during acupuncture treatment is further supported by the findings of increased concentrations of cholecystokinin (CCK) in both animals and humans during anxiety and panic attacks (Cohen et al., 1999
). Since CCK is an endogenous opioid antagonist, increased concentrations may reduce or completely negate the positive effects of acupuncture treatment. Recently it was reported that anxiety decreased pain thresholds (Rhudy and Meagher, 2000
).
The therapeutic response depends on the complicated interaction between patient factors and expectations, therapist factors and expectations, and treatment factors, including the specific and non-specific effects of treatment (Filshie and Cummings, 1999). In conclusion, treatment outcome depends on the patients responsiveness to the whole of the therapeutic encounter (Thomas and Lundeberg, 1996
).
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Is there evidence for the use of acupuncture in reproductive medicine? |
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Circulatory effects of acupunctureuterine artery blood flow impedance
The cardiovascular effects of acupuncture have been extensively studied and can be referred to a clinical area where trials already exist. Successful IVF and embryo transfer require optimal endometrial receptivity at the time of implantation. Blood flow impedance in the uterine arteriesmeasured by transvaginal ultrasonography expressed as a resistance index, the pulsatility index (PI), distal to the point of samplingis considered valuable in assessing endometrial receptivity. In an uncontrolled study (as pointed out by Renckens) we showed that repeated EA treatments reduced a high PI value in the uterine arteries to normal levels (Stener Victorin et al., 1996). This is an interesting finding, but comparative RCTs with conventional treatments, such as low-dose aspirin, are needed.
EA as anaesthesia during oocyte aspiration
Renckens (Renckens, 2002) wonders whether the use of EA as anaesthesia during oocyte aspiration still persists in Gothenburg (Göteborg). Yes it does, as a method of pain relief during oocyte aspiration, and it works extremely well for patients who prefer trying this option to alfentanil. That EA induces adequate analgesia during a minor operation is not a new observation and can be referred to a clinical area where trials already exist (Ernst and Pittler, 1998
). We therefore chose to compare EA with conventional anaesthetics (Stener-Victorin et al., 1999
), and we have recently finished a multi-centre follow-up study with 280 patients. These studies show that EA is as good an anaesthetic method as conventional anaesthetics during oocyte aspiration. In addition, women who received EA have less abdominal pain and nausea and were less stressed 2 h after aspiration. EA in combination with conventional anaesthetics has been shown to reduce the consumption of anaesthetics by 50% (Wang et al. 1994
). Such a reduction is most likely preferable because the fast acting opiate, alfentanil, has been found in the follicular fluid shortly after i.v. injection (Soussis et al. 1995
). In conclusion, EA is a valuable alternative or complement to conventional anaesthesia during oocyte aspiration.
Acupuncture effects on hormonal disturbances such as PCOS and anovulation
Most studies in this area use the approach of a trial of single intervention with variables analysed on an intention-to-treat basis. Unfortunately, poor design and a lack of valid outcome measures and diagnostic criteria, which make it difficult to interpret the results, flaw most of them. The studies all report favourable outcomes such as ovulation induction; a regulatory effect on gonadotrophins, estrogens, and neuropeptides; and a tendency, for example, for miscarriage rates to be lower compared with hormonal treatment (Chen and Yu, 1991; Gerhard and Postneek, 1992
; Xiaoming et al., 1993
).
Recently, we conducted a study on women with well defined and diagnosed PCOS and anovulation to elucidate the effect of repeated EA treatments on endocrinological and neuro-endocrinological parameters as well as on anovulation (Stener-Victorin et al., 2000). This study showed that repeated EA treatments exert long-lasting effects on both endocrinological parameters as well as anovulation. These results are in accordance with previous results, but it is obvious that randomized, comparative studies are needed to verify the results and to exclude non-specific effects. However, these studies do not enlighten possible underlying mechanisms of EA. These are, for obvious reasons, difficult to study because tissue samples from the ovaries and central nervous system are unobtainable.
Experimentally induced polycystic ovaries (PCO) by a single i.m. injection of estradiol valerate (EV) in rats share many endocrinological and morphological characteristics of human PCO. Therefore, we used the steroid induced rat PCO model to investigate the effects and possible mechanisms of repeated EA treatments during light anaesthesia by analysing CRF (Stener-Victorin et al., 2002) and nerve growth factor (NGF) (Stener-Victorin et al., 2000
) in the ovaries, the adrenal glands, and the central nervous system. The results indicate that EA modulates activity in the sympathetic nervous system and that there is a functional interaction between activity in the nervous and the endocrine systems.
In conclusion, it appears that acupuncture may have a beneficial effect on women with PCOS and anovulation, supported by both clinical and experimental evidence. Therefore, acupuncture may be a suitable alternative or complement to pharmacological induction of ovulation in a woman with PCOS, with no negative side-effects. However, there is a need for more RCTs in well-defined diagnoses.
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Conclusion |
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We do agree that there are few well-designed papers on the effectiveness of methods of treatment that are not generally established in Western medicine, but we do not agree that it can best be summarised as much ado about nothing. We need to stick to basics and to have open scientific minds. We hope that this also applies to the readers of the present debate article.
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Notes |
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References |
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