Acupuncture Beyond The

Medical Hypotheses (2002) 58(3), 221±224

& 2002, Elsevier Science Ltd. All rights reserved.

doi: 10.1054/mehy.2001.1425, available online at http://www.idealibrary.com on1

Acupuncture beyond theendorphin concept?

I. L. Bonta

Emeritus Professor of Pharmacology, Erasmus University Rotterdam, The Netherlands

Summary Traditional acupuncture has been used for treating a variety of health conditions. In contrast, Western

physicians limited acupuncture to the alleviation of pain. Concomitant with a recent view that not all kinds of pain are

within the reach of acupuncture-induced relief, it has been suggested that some conditions other than pain can be

effectively treated by this method. Increased release of the neuropeptide b-endorphin was proposed to explain the

antinociceptive function of acupuncture. Even if correct b-endorphin cannot account for the effect of acupuncture in

other conditions. Endorphins might be interacting with cytokines, some of which (e.g. interleukin-10) downregulate the

inflammatory component of disorders in which acupuncture may be useful. We present a speculative notion of the view

that acupuncture may amplify the interaction between neuropeptides and cytokines. A non-invasive approach, such

as immune-committed cells harvested from blood of acupuncture-treated patients, could be used to examine this

hypothesis. Inclusion of a placebo group might support the credibility of acupuncture. & 2002, Elsevier Science Ltd.

All rights reserved.

ANTINOCICEPTION: THE ORTHODOX WESTERN

VIEW ON ACUPUNCTURE

Acupuncture is among the most ancient therapeuticinterventions of mankind. Widespread views date theroots of this procedure as being some 3000 years ago. Butit appears that acupuncture must have been practiced atleast 5200 years ago (1). On the skin of the oldest Eur-opean mummified human body, the so-called TyroleanIceman, tattoos have been found on the back and legs.The linear geometry of the locations of the points closelycorresponds to acupuncture points used to treat arthrosisof the lumbar spine. Computer tomography revealed thatthis person indeed suffered from this condition. Whetherthe archaic Central European acupuncturist had anycontact (by which means?) with colleagues of the Far East,or was operating independently, is a cultural anthro-pological issue beyond the scope of this paper. Which

Received 9 January 2001

Accepted 25 May 2001

Correspondence to: Ivan L. Bonta, Hanegev 6, 42304 Netanya, Israel.

Phone: �972 9 8622205; E-mail: [email protected]

other ailments, besides arthrosis, were the target of theancient Eurasian acupuncturists is unkown as yet. But inthe Far Eastern traditional history of acupuncture, theindication field of this medical art comprises a very widescale of health conditions, ranging from psychologicalcomplaints to ailments which ± at least by modern medi-cal standards ± would need surgical intervention. In con-trast, the majority of Western physicians were, until thelast two decades or so, reluctant to employ acupuncturefor purposes other than the relief of pain. This is under-standable because many of the reports which showedbeneficial effects of acupuncture outside the anti-nociceptive influence were the outcome of poorly docu-mented uncontrolled trials, occasionally anecdotical or atbest equivocal.

The use of acupuncture for pain relief is now unmis-takably well documented both in physiological trials onhealthy volunteers (2) and in controlled clinical trials onlarge series of patients (3,4). Also it is clear now that thepain-relieving effect of acupuncture is a specific one, nottowards random pain of indiscriminate origin. In supportof this is a recent paper which indicates that certainkind of pain, e.g. that which accompanies HIV-related

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222 Bonta

neuropathy, is outside the reach of acupuncture-inducedantinociception (5).

As for the physiological basis of pain relief by acu-puncture, at present it is common knowledge that thiseffect is largely mediated via increased release of endo-genous opioid neuropeptides; the endorphins (6). It wasshown that the induction of analgesia by acupuncture isaccompanied by increased cerebrospinal fluid (CSF) levelsofb-endorphin fromthepituitary±hypothalamic region (7).Furthermore, coadministration of the opiate antagonistnaloxone annihilates theacupuncture-mediated analgesia.

ACUPUNCTURE OTHER THAN FOR PAIN

The impressive increase in the use of acupuncture as atherapeutic intervention, even for poorly defined condi-tions, recently prompted the US National Institute ofHealth (NIH) to organize a consensus conference on acu-puncture (8). The objective was to provide clinicians andpatients with a responsible assessment of the use andeffectiveness of acupuncture to treat a variety of condi-tions. Without any pretention for completeness the mostimportant indications (besides pain control) which werepositively recommended will be briefly discussed below.

There is clear evidence that needle acupuncture is effi-cacious for adult postoperative and chemotherapy-induced nausea and vomiting, and probably for nauseaduring pregnancy (9). Significant studies were devoted tobronchial asthma, suggesting that acupuncture decreasesthe airway resistance in asthmatic patients (10,11). Whilean immediate short-lasting effect following acupuncturewas most evident, a longer-lasting effect was not excluded.Encouraging effects have been reported in musculo-skeletal disorders, such as neurological damage (12)and the immunoinflammatory condition rheumatoidarthritis (13). Somewhat ambiguous were the effects inobese patients (14,15). All these are widely different clin-ical conditions. Still there is one common denominatorwhich binds them together: there is an incompleteaccount of the endorphin concept itself for the influenceof acupuncture alone or as adjunct therapy in thesedisorders.

ENDORPHINS ARE MORE THAN JUST

ANALGESIA

There is evidence that acupuncture, a manipulationremote from the brain, has an effect on the central ner-vous system (CNS). Animal experiments have shown thathypothalamic nuclei have a central role in mediatingthe effect of acupuncture (16). Lesions in the nucleusarcuatus eliminate the analgesic effects of low-, but not ofhigh-frequency electro-acupuncture and increase in theb-endorphin level has been observed in brainstem tissue


of animals after acupuncture. In addition, other observa-tions have shown that acupuncture has an influence onspinal-cord opioid receptors (17). A study on healthyvolunteers suggests that acupuncture may affect thesympathetic system (2), and that this effect is mediated viamechanisms at hypothalamic levels (18). In turn thehypothalamic b-endorphinergic system may be importantnot only in pain control but also in the regulation of bloodpressure and body temperature. Accordingly, acu-puncture, via the endorphin system, may have effects onautonomic functions.

Another effect of acupuncture, besides the anti-nociceptive function, includes inhibition of gastric acidsecretion (19). Again however, this is mediated via b-endorphin. Interestingly, b-endorphin is not the onlyneuropeptide which is released following acupuncture(19,20). Increased levels of vasoactive intestinal peptide(VIP), calcitonin gene-related peptide (CGRP) and neuro-peptide Y (NPY) have been detected in saliva after acu-puncture stimulation. The functional importance of VIP,CGRP and NPY is not well understood, but it is unlikelythat their role is limited to nociception. This is in favour ofmechanisms which may underlie the effects of acu-puncture beyond pain control.

COUNTER-IRRITATION AND ACUPUNCTURE

This is the appropriate place to discuss the time-honoredphenomenon of counter-irritation, and compare it withacupuncture. The two issues share not only some of theunderlying physiological mechanisms, but also the con-troversial medical opinions surrounding them. Muchinformation on counter-irritation has been presented atlength in a review (21). The process of counter-irritationessentially consists of combating pain and/or inflamma-tion at one site of the organism by irritating a remotesite of the same organism. While possibly younger thanacupuncture, it still is a very old medical art, whichwas advocated for the treatment of inflammation andrelief of pain.

In animal experiments a large variety of chemical irri-tants have been used to induce the pain-relieving effectsof counter-irritation, but in humans chemical irritantswere less effective for this purpose than physicalirritation. Some analogy between counter-irritation andacupuncture was proposed more than 20 years ago (21).More recently a full paper has discussed parallel physio-logical aspects of the two procedures (22).

As the practice of acupuncture essentially consistsof placing needles subcutaneously at certain bodysites remote from those at which pain suppression or down-regulation of immunoinflammatory processes or eventu-ally some other noxious event occurs, the resemblance tocounter-irritation is evident. There are several variants of


Acupuncture beyond the endorphin concept? 223

acupuncture, but even the simplest procedure, whenproperly exerted, requires local manipulation of the needleuntil the patient feels the renowned Qi (`chi') sensation (adeep cramp-like feeling). Both manipulation of the needlein situ and electroacupuncture produce local tissue-irrita-tion, and the analogy with counter-irritation is indeedstriking. Counter-irritation triggers the local and remoterelease of humoral factors (21) and so does acupuncture.

The release of endorphins is a plausible explanation forthe relief of pain, but what factors might be discharged toaccount for the beneficial effect of acupuncture in bron-chial asthma or rheumatoid arthritis? Both these condi-tions comprise immunoinflammatory components, hencethe answer should be sought in some factor which is rela-ted to inflammation, more explicitly a mediator of inflam-mation. The proposal presented here is that this factor isconceivably the cytokines, because some members of thisgroup of mediators are interacting with b-endorphin.

CYTOKINES INTERACTION WITH

NEUROPEPTIDES

Cytokines belong to the mediators of inflammation.More than 50 cytokines have been identified and allof them are peptides. Those cytokines which are impli-cated in inflammatory and immune conditions are pro-duced mainly from macrophages and lymphocytes.Some cytokines are proinflammatory, but others areantiinflammatory. The interleukins include an importantgroup within the cytokine superfamily (23). The anti-inflammatory interleukins comprise interleukine-4 (IL-4)and interleukine-10 (IL-10) and these are considered asmediating the down-regulation of immunoinflammatoryconditions (24±27). However, the function of cytokinesis not limited to the immune system. It was shownthat cytokines can regulate the pituitary release ofb-endorphin (28). On the other hand, besides nerve tissue,immune cells are also sources of b-endorphin (29), whichdirectly or indirectly (via the immune cell derived cyto-kines) may have an influence on inflammation. Neuro-peptides other than endorphins have also been shown tostimulate lymphocytes (30,31). In turn, IL-10 down-regulates lymphocyte function (23). b-endorphin hasrecently been shown to participate in the control of localnociception governed by selectins, which are cytokinespromoting the adhesion of immune-committed cells (32).Direct interaction between b-endorphin and selectins hasnot been studied.

CAN CYTOKINE INVOLVEMENT IN

ACUPUNCTURE BE TESTED?

Provided that neuropeptides and cytokines mutuallyinteract with each other's release and function, this could


form the basis for the speculative notion that acupuncturemay amplify this interaction. In turn, such a conceivablephysiological process could account for the effect of acu-puncture in immunoinflammatory conditions such asbronchial asthma and rheumatoid arthritis. However, anyhypothesis awaits to be tested. With experiments in whichhumans are involved non-invasive approaches are pre-ferred. For testing the present hypothesis, immune-com-mitted cells, such as T-lymphocytes or monocytes, ex vivoharvested from the blood of acupunctured patients couldbe used. Acupuncture is anyway known to result in anincrease in blood white cell count (33). Accordingly nodifficulties could be expected for obtaining sufficientnumber of cells to test the proposal.

PLACEBO EFFECT: A CRUCIAL MATTER

Regarding a trial design for testing an acupuncture-relatedproblem, there is the matter of an appropriate controlgroup. In this context the point is not that acupuncturedoes not work in a number of situations. Certainly it does.But it has to be kept in mind that there is a placebocomponent which must not be underestimated. Indeedit has been argued that placebo effects are potent to suchextent that they can mimic not only the acupuncture-induced antinociception, but also other effects of acu-puncture such as inhibition of gastric acid secretion (34).In this context it has been suggested that acupuncture ispossibly a uniquely effective method in the activation ofpositive placebo effects (18). The effects of placebos mayreflect the capacity of an individual to recruit the endo-genous opiate peptide system (35). Accordingly, endor-phins may be released in response to placebos.

In view of the interaction between endorphins andcytokines (28,29), there is no reason to disbelieve thatrelease of cytokines could occur during placebo-mediatedeffects of acupuncture. In order that these events be cal-culable, a placebo method of needling ± with the samepsychological impact, including the Qi sensation ± asactual needling is required. A placebo needle which meetsthe above criteria has recently been developed (36) andshould be included in a trial as proposed. Such studiesmight not only serve to support the credibility of acu-puncture, but also to uncover additional areas where thisprocedure might be of benefit.

ACKNOWLEDGEMENTS

Amos D. Korczyn (Professor of Neurology, Sourasky MedicalCenter and Sackler Medical School, Tel Aviv University, Israel)contributed to the placebo section of this paper. JoeÈ l Rak(Professor of Anatomy and Anthropology, Tel Aviv University),who is a disbeliever of acupunture's efficiency, was kind enoughto read and discuss the paper.


224 Bonta

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Acupuncture Beyond The