There seems to be a general consensus within the acupuncture and Chinese herbal community that research is a necessary process to establish our professional status. It may be regarded as a ‘good’ thing, a bold venture to bring Chinese medicine into the cosy confines of evidence based medicine; or perhaps more cynically ‘a necessary twenty-first century evil’ that we need to grit our teeth and get on with. This is an account of my foray into the research world to explore the role of Chinese herbal medicine (CHM) in the treatment of endometriosis. I set off on my journey dressed in a shiny suit of optimistic positivist fervour. Now several years down the line I feel more like Don Quixote lining up my intellectual lance and charging heroically towards the next windmill on the horizon. This then is the story of how a naive would-be knight lost his armour, encountered the dark forces of bureaucracy, and depending upon your point of view either grew up or went quietly nuts.
In The Beginning…
Where does the desire to do research originate and who is it for? For me it emerged from a simmering desire to prove Chinese medicine (CM) to the arrogant disbelieving doctors who inhabited the outer worlds of the popular press, medical journals and textbooks but who had, rather irritatingly, also taken up residence in some well defended corner of my own mind. In the beginning then, it was simple. Let’s see if CM works and use research as the tool to prove it and banish these demons once and for all.
And so I embarked on the quest. First stop was a grant provided by the Research Council for Complementary Medicine looking at audit for complementary and alternative medicine (CAM). There were lectures, workshops and discussions to define audit and explore how the audit cycle could be used in our clinics, but my imagination failed to soar at the prospect of how I could use these techniques to enhance my letter writing to GPs or improve my case notes. Surely audit belonged more to its natural home of accountancy rather than the brave new world of CAM research.
Then, out of the shadows, emerged the glittering prospect of an ‘outcomes audit’. None of this namby-pamby form-ticking introspection. Here was something altogether more muscular and relevant. I unearthed MYMOP (Measure Yourself Medical Outcomes Profile), a validated outcomes measure developed by the wonderful GP researcher Charlotte Patterson and I took my new treasure to London Lighthouse where I was working with people with HIV and AIDS. Now using self-reported, patient-centred outcomes measured on a simple 0-6 Likert scale I could demonstrate the effectiveness of CM in action. The only problem was that it didn’t quite work out like that. Patients seemed to be doing well but had a rough journey getting into the clinic so they reported they were feeling worse. Those who to me seemed to be going downhill fast reacted either with a noble stoicism or to please their earnest acupuncturist and reported significant improvement. At the end of the day I had 18 cases and could demonstrate considerable improvement in a number of these cases. Job done, surely. Unfortunately I knew that what I had recorded was a very blurred, two dimensional map of a highly complex multidimensional world. Audit was no grail and so the quest had to continue…
Entering the Lions’ Den…
There was obviously no alternative. It was PhD or bust. At the time, the mid-nineties, Professor Ernst had appeared, Moses-like, on the scene as the first professor of CAM based at Exeter University; surely a natural home for an aspiring researcher. I spoke to the Prof. He listened politely and then congenially told me to go away and learn Chinese and come back when I was suitably proficient to read the Chinese medical literature. The phone grew heavy in my hand. I was in the process of leaving a Chinese language course at London University which was more focused on ordering a bowl of noodles than examining the effect of these noodles on the GI tract, so this struck me as a rather weighty demand. Still, no quest is complete without its detours, and it was back to private language lessons under the gentle tutelage of Ji Liang on a weary Thursday evening after a long day’s clinic where I really experienced the meaning of spleen qi deficiency. To this day I am grateful to Prof Ernst for his advice (and Ji Liang for her patience). Learning to read medical Chinese, even badly as I do, is, for me, one of the essential lessons of the quest.
A few years pass. The intrepid researcher is starting to look increasingly dishevelled and directionless. Distracted by the politics of the herbal world and the demands of making a living, the quest is starting to wobble. And then a gentle reminder from the esteemed House of Lords of the need for the quest when a report is published that seems to accept acupuncture but places CHM in the same superstitious, deluded category as crystal healing (no offence intended). 2000 years of written medical literature, over 10,000 (admittedly methodologically weak) randomised controlled trials (Tang,1999) reported in Chinese medical journals, my own and others clinical experience in the West… no evidence base…? The red mist descends once again and a trusty steed employed (SW Railways) to take me to a CAM research conference in Southampton.
It is here that I encounter Dr George Lewith and a group of very impressive researchers talking in an occult language of p values, confidence intervals and power calculations. The truth detector starts to hum. But Dr Lewith sends me back to school. An MSc in research methods is now required and I'm starting to feel like something out of a Monty Python Zen movie where the novice is asked to demonstrate commitment by severing one limb after another before entering the temple, only to find on acceptance he has no means of moving across the monastery threshold.
Like the first detour, however, this one proves to be a useful experience. The mysteries of statistics and qualitative research are explained, open-minded doctors are encountered and befriended, and the tools of research design first encountered. And yet, even in the heart of the lions’ den, I am amazed by the lack of a well-conceived philosophical basis to the research process. Amongst all the sophistication of research technique no one seems to be overly interested in the status of what is being discovered. Research is implicitly taken as a way of establishing the truth about an intervention but questions about which and whose truth are seen as bordering on heretical. A paper is published in the BMJ (Campbell, 2003) demonstrating a positive quantitative outcome after knee surgery, but a nested qualitative study involving in-depth interviews of the same patients revealed incredible discrepancies between the quantitative outcomes measures and the verbal reporting of the trial participants. The fact that quantitative measures, beloved of the statistician, may only measure one truth and may even distort another is an uncomfortable prospect that is rather astonishingly ignored. The authors of the heretical paper have received hardly any formal enquiries about their data. Surely this noble pursuit of unbiased truth cannot have its own bias?
Beginning the Ascent…
I am rescued from the second year of the MSc by the grandiosity of my own dissertation ambitions: A feasibility study exploring the role of CHM in the treatment of endometriosis. Dr Lewith (now Uncle George) tells me this is a PhD project and after a brief flurry of emails I become a PhD candidate. I feel like I have just had my research bar mitzvah.
I am now given the task of exploring the conventional pathology and treatment of this disease. I enrol at the British Library and bask in the glow of endless lines of medical journals, limitless access to more journals via the Internet, and the ghost of Karl Marx and other less ethereal researchers unstinting in their pursuit of knowledge and truth.
I now have enough material to spend the next few months processing. I find out that no one really knows how many women have endometriosis or what really causes it. We can reckon on ten per cent of women of reproductive age suffering from the classic symptoms of dysmenorrhoea, pelvic pain, pain on intercourse, urination and bowel movement. Around 30 per cent of these women will have problems conceiving and many of them will experience a debilitating fatigue that, together with the symptoms of pain, drains the quality from their lives. There are different theories about the aetiology of endometriosis. Enduring theories like retrograde menstruation leading to hormonally responsive endometrial cells taking root and continuing to proliferate in the pelvic cavity are complicated by the fact that 90 per cent of women exhibit this phenomenon. What is clear about this ‘enigmatic’ disease is that its causation is a complex mix of genetic, immunological, hormonal, environmental and even (!) psychological factors.
Western medical treatment is either medical or surgical. Medical treatment ranges from symptomatic control with non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics, through to treatments that aim to suppress the normal ovarian production of oestrogen by either hormonally simulating pregnancy (continuous oral contraceptives (COCs) and progestins) or menopause (danazol and gonadotrophin-releasing hormone agonists (GnRH-as)). Side effects from these drugs are unpleasant and include hot flushes, weight gain, acne and osteoporosis. Having endured this ordeal women are faced with the high probability that symptoms commonly return once treatment stops.
Surgical intervention can be either ‘conservative’, involving the usually laparoscopic removal of endometrial lesions, or ‘definitive’, involving the removal of the uterus and ovaries. But relief from surgery is also usually relatively short-lived with symptoms returning in 44 per cent of women after one year (Sutton,1997) and up to 75 per cent of women after two years (Giudice and Kao, 2004).
In a nutshell: endometriosis is a frustrating and difficult illness.
But my experience as a CM practitioner treating women with endometriosis is slightly different from the reality expressed in the western medical journals. It seems to me a difficult disease but one that is responsive to Chinese herbal and acupuncture treatment. Pain seems to recede, vitality improves and women emerge from home confinement back into useful and enjoyable lives. Another tenet of CAM research: pick an illness that western medicine doesn’t treat very well but that appears responsive to an alternative intervention.
The conventional terrain has now been mapped. Surely now it will be easy to carve out a research pathway for CHM and endometriosis…
This is when the pathway starts to become a maze. First of all, given that endometriosis doesn’t strictly exist within pre-surgical classical CM how do we define it for the purposes of this study? Is it appropriate to follow the lead of the Chinese medical journals and take the disease categories of painful periods, abdominal pain, infertility and mix in a little treatment of abdominal masses (zheng jia) to produce a modern model for endometriosis aka zi gong nei mo yi wei? Or is endometriosis a new disease? Do you need to make a palpatory diagnosis for abdominal masses or will a laparoscopic image suffice? How much are the contemporary accounts of endometriosis in the Chinese medical journals influenced by biomedical understanding of disease and is this a problem? These are big questions for a little researcher…
Personally I take a pragmatic approach. Practitioners of Chinese medicine have been knowingly treating endometriosis over the past 30 to 40 years. It is this experience that I will use to provide good practice guidelines to inform my trial. The howls of the traditionalists echo mournfully over the research tundra…
Why do we need good practice guidelines? Isn't it enough to research what I'm already doing? For me the answer is 'no'. With research comes responsibility. What I do has a bearing on your practice. If I screw up then all of us will be bathed in the same scathing publicity. If I strike gold then I could be looking at a life membership of the Register of Chinese Herbal Medicine (RCHM) and CM will become an acceptable, well-known option for the treatment of endometriosis. So I need to plumb the depths of understanding about endometriosis, to explore the different diagnoses and become familiar with the range of treatment strategies. This is the intelligence gathering exercise. Researcher as spook.
I choose three paths to lead to the minor peak of good practice guidelines. A review of the available Chinese research literature (thank you Prof Ernst!), a consensus generating process known as Delphi to be conducted with experienced practitioners in the west, and reflection on my own clinical experience. I have written a full review of Delphi elsewhere (Flower et al, 2007) but the basic idea is to generate key statements about the treatment of endometriosis and then send these to selected practitioners and ask them to rate their level of agreement from 0 (completely disagree) to 7 (completely agree). This process is repeated until there is little or no change in the rating, at which point it can be said a consensus has arrived. Delphi is a practical and anonymous way to ask people to share their experience free from the influences of peer pressure and having to maintain ‘face’. I ask practitioners to comment on statements relating to diagnosis, treatment, herb selection, dosage, patient management and prognosis.
It sounds good and reads better but Delphi struggled to live up to its name. Statements require nuanced answers that defy a simple numerical response, participants were reluctant to reconsider their original opinion, and although all opinions have value, some have more value than others. Nevertheless something useful emerged from the exercise and I leave the oracle with a Delphi-derived differential diagnosis of endometriosis that definitely furthered my understanding of the illness.
However the utterances of oracles are notoriously ambiguous. I needed to cross-reference Delphi with another group of expert practitioners. These practitioners could be found hiding within the camouflage of Chinese characters taken from 55 papers describing the treatment of endometriosis. These data were slowly and painfully decoded and entered into my first ever database. Diagnostic categories seemed to correlate and similar herbs were selected for the same syndromes. This was not completely unexpected but it warmed the icy cockles of my research heart and propelled me forward into the next great obstacle in the quest… the brick wall of bureaucracy!
The Land of Mordor!
Apart from the eczema trials (Sheehan and Atherton,1992) of the early 1990s, famous both for their positive findings and for the splendour of their isolation in the UK CHM research portfolio, there have been no other serious trials into CHM in the UK. To do any kind of clinical research now requires the ability to morph into a fully-fledged civil servant. For herbal medicine you will need approval from the Medicines and Healthcare Products Regulatory Agency (MHRA) to use an Investigational Medicinal Product (IMP), ethical approval from one of a number of possible ethical boards and, if you want to interface with the NHS, Research and Development (R&D) approval. Each one of these processes requires an almost unbelievable amount of form-filling and supportive paperwork. Most CAM practitioners operate at the anarchic end of the organisational spectrum and to encounter this level of bureaucracy is an unsettling and painful shock to the system. (To my wife, an NHS employed occupational therapist, this level of brain numbing paperwork is the norm!)
One of the problems is that herbal medicine doesn’t fit into the categories that have been designed for pharmaceuticals. The MHRA and ethics committees just couldn't get it that trial participants would be getting individualised prescriptions that would also change every couple of weeks. A clinical trial tests one thing surely, not a list of 80 or so commonly used herbs in the treatment of endometriosis. Once we had established that herbs could be considered an IMP there was the problem of providing quality assurance and safety data. Did we have Good Manufacturing Practice? But herbs aren't manufactured. OK then, how about Good Agricultural Practice? Well no one has that and we're all happily using these herbs to treat sick people…
Following the Delphi process, individual and combined syndromes can be grouped into three categories reflecting how
commonly they present clinically:
Category A – most common
Category B – less common
Category C – rarer presentations/presentations favoured by individual panel members
Heat in the Liver channel
Kidney Yin deficiency
Kidney Yang deficiency
Spleen Qi deficiency
Qi and Blood stasis with Qi and Blood deficiency
Qi and Blood stasis with Cold In the uterus
Blood stasis from Cold, Kidney Yang deficiency and Damp
Qi and Blood stasis with Kidney Yang deficiency
Qi and Blood stasis with no signs of deficiency
In the end, pharmaceutical data from the Materia Medica and the assurance of quality from the RCHM's Approved Supplier scheme seemed to allay some of the concerns. And then the grinding cogwheels of the trial became derailed by the MHRA who wouldn't approve it after all and gently implied that we spend around £100,000 to ensure pharmaceutical grade GMP standards. I had a now familiar feeling of being switched off, of losing the desire to research and wishing that I could let the whole blasted trial sink back into the murky swamp that it had emerged from. But then (God bless the liver!) frustration turns to anger and phone calls are made spiralling up the MHRA hierarchy until eventually a cool and reasonable voice is found and the project is breezily rubber-stamped and I am sent off to face the Ethics Committee clutching my MHRA approval in a bloodied and shaking hand.
Actually almost every researcher I have spoken to has found this whole process incredibly gruelling and pedantic. Chinese medicine is unfortunately out of the mainstream box and the people on the other side of the bureaucratic fence don't understand it, have the horror stories of liver and renal toxicity echoing in their minds, and don't want to find themselves pilloried for having given credibility and exposed NHS patients to something that sounds like it has emerged from a Hogwarts classroom.
My encounters with the Ethics Committee makes the MHRA seem like a summer picnic. It's difficult to describe why it is such a painfully tedious process to go through. Like childbirth, I am told, the painful memory recedes back into some poorly accessed protective file in the mind. There's something about the seemingly endless paperwork that is mind-numbingly boring and demotivating. Each form seems to require several other mini forms and supportive letters, and the euphoria of sending off the final package is shattered by the request from the next bureaucrat on the food chain who wants his pound of complementary medical flesh. You need MHRA approval to get ethical approval but before you get ethical approval you need the approval of a sponsor, who in turn needs the assurance of funding, the written confirmation of a peer review and insurance. Insurance requires… bureaucracy expects… and a kind of mental hypothermia sets in that destroys the investigative imagination. What's going on here? The people operating these systems are nice enough but there is a sickness in our culture that has taken sensible precautions and warped them into paranoid overly controlling mechanisms to stop 'something bad' from happening and to ensure that if 'something bad' does happen, individual and organisational backs have been well covered.
Eventually the forms are completed, all the hoops jumped through and now there is only the Ethics Committee meeting to face; surely a benign bunch of do-gooders who will rub their monocles, adjust their teeth and give me the final approval I now need to actually start recruiting a real life patient. Only, once again, it isn't quite like that. The committee is filled with consultant anaesthetists, public health directors, renal specialists, GPs, and only one woman with a blue rinse (who turns out to be a frighteningly intelligent statistician). They are very sharp, legally liable for any problems from the trial and they aren't going to let some superstitious nonsense get through their committee without a decent fight. My proposal is rejected but a lifeline of amendments thrown to me which I spend the next few months putting into place. Another meeting is convened. This time I bring reinforcements and I unleash my supervisor, the rather formidable Dr Lewith, onto the Committee who seems to herd them into acceptance by force of will and a flash of intellectual fang.
I have MHRA approval, ethical approval, and R&D approval (a relative synch). I am ready to begin. It has only taken a year and a half of my life so far!
Another serious point here: if you are inspired to take the research quest, for the sake of your finances, relationships and your sanity, make sure that you get the support of a university, attentive supervisors and, ideally, funding to take you forward. It is a laborious, frequently demoralising, and time-consuming process and one of the few solaces gained during my journey through ethics was an awareness that the Department of Health was paying for the pleasure of my time.
The Phoney War
I felt genuinely euphoric when the final approval arrived from ethics. Now we could surge ahead with patient recruitment and treatment. My study is only a small feasibility study requiring 48 women who would then be randomised into an active group (A), a placebo group (B) and a waiting list control group (C). By comparing group A with B we would get an idea of the specific effects of herbal treatment and by comparing B with C we would get an idea of the non-specific effects which occur as a result of having a consultation, getting a diagnosis, receiving a remedy and so on.
One of the problems of research that starts almost immediately and runs through the trial is the tendency of the research process to distort what is being investigated. If you want to do a double-blind randomised controlled trial (RCT), most herbal research tends to contrast an active encapsulated powder or pill with an inert starch placebo. The problem with this, in my case, is that I barely use encapsulated or any other form of concentrated herbal powder. My own and others’ clinical experience and some research from Australia (Xie, 2006) testify to the enhanced effectiveness of a herbal decoction. To use powders was a compromise I was not prepared to make. (I wonder how many acupuncture trials are deeply flawed by the practical difficulties of using moxa in the protocol?) I needed a placebo that would resemble a decoction in appearance and taste, but without any significant pharmacological activity.
I convened an Internet group of experienced western herbalists and eventually managed to develop and successfully test a mixture of dried vegetables and culinary herbs that tasted fairly foul but, according to the literature, should be relatively therapeutically inert. Only… nothing is completely inert. Too much water can kill. I know when I write up this trial the placebo is going to be a battlefield of contention. My argument will be that this inertia is relative and that an active herbal formula should be able to show significantly more effect than a glorified vegetable soup.
Next step: recruitment. I had managed to involve a sympathetic local consultant gynaecologist who specialised in the treatment of endometriosis. Recruitment was not going to be a problem. A database with several hundred suitable candidates was promised and I waited eagerly for its arrival so that letters of invitation could be mailed out. I waited a bit more. The consultant was on holiday… his secretary was off sick… who was I again…? Weeks turned to months and finally, after I organised a campaign of harassment bordering on the criminal, the list arrived. Only there was no database. Instead copies of 200 letters sent several years ago arrived on my computer with a vague apology and a message wishing me good luck. Addresses were transcribed. Out went the mail, in came a few interested enquiries but the few stayed as a few and even they didn’t seem willing to sign up to the trial.
This was really depressing. To fight through the bureaucracy and then to wake up to the illusory nature of the cherished interface between myself and the hordes of NHS patients (who would leap into a trial offering free complementary medicine) was not a comfortable moment. Maybe the problem was the consultant, not the approach. Three more consultants were contacted. All expressed an interest, more ethics and R&D applications flew joyfully off my laptop, and yet not a single patient was delivered to my doorstep. Why was this? Probably because they were too busy, although the first consultant took an unseemly amount of time off for a busy man; possibly because they didn’t want to be tainted by involvement with complementary therapies; maybe because they didn't want to waste their patients’ time… Whatever the reason, if you ever hear a consultant bemoaning the lack of CAM research give them a slap from me.
However, as is often the case, failure becomes the springboard for new ways to success. A colleague mentioned the trial at the annual jamboree held by the voluntary group Endometriosis UK. Suddenly interested emails started to arrive. A few people enrolled. Then we managed to get an article in the Saturday Times and there was another flurry of interest and a few more enrolments. Endometriosis UK posted details on their website, a few other magazines covered the story and gradually, ever so gradually, the trial started to fill up. We now have 40 people signed up for the trial. Still some way away from the 48 we were looking for, but we have moved out of the disaster zone.
This part of the quest continues to be difficult but it is also rather fascinating. Once the conventional NHS route failed I was forced to find a different approach. The Internet and the media provide an alternative, rather subversive, route to bypass the conventional routes of referral and speak directly to the patients. If I ever find the time and will to do this again, this is the approach I will insist is written into the protocol.
I now know why a trial is called a trial. It is hard work. You are examined, cross-examined and judged as much as the participants. Even so it has been a fascinating process becoming a practitioner researcher for a number of pleasant and not so pleasant reasons.
After so much whinging about the hardships encountered in my quest I feel that any resilient reader still hanging on in there deserves a bit of good news. It is wonderful to be able to offer free treatment and to encounter people who would normally be financially excluded from CM. Some of these people have experienced real benefit from treatment and I just hope to God they are in the active and not in the placebo group.
That's the good news dealt with. The not-so-good news is that treating people within a research context is different from normal clinical practice. First of all, there is a minor mountain of paperwork to go through before you've had the chance to make proper eye contact and establish the rapport that most of us take for granted. Consent forms need to be signed, outcomes measures need to be collected, checked and initialled, inclusion criteria need to be ticked, a questionnaire to assess the trial's blinding completed… Having this paperwork in strategically placed piles on my desk is a major achievement. Filling it all in and establishing a normal rapport is a minor miracle. And then there's randomisation. Sending people in obvious pain off to the limbo of the three-month waiting list control group was hard. It goes against the grain and I hated doing it. I think, unsurprisingly, the women hated it being done to them too and, after an over 50 per cent drop out from this group, I decided to suspend this arm of the trial.
The process of randomising people to active or placebo is more subtly disturbing. Both patient and practitioner are blinded to this randomisation. The women in the trial do not know which group they are in and neither do I. This is a strange intrusion into the standard therapeutic encounter. You have your suspicions about who is on what, but you have to assume everyone is on the active herbs and make the appropriate changing prescription noises when symptoms appear unchanged. There is no doubt that, when I suspect someone is on the placebo I have to fight against taking less care when I write their prescription because I don’t really believe it will see the light of day. All this introduces an element of dishonesty or trickery into the consultation that I dislike and which I am sure has a negative impact on the patient’s outcome.
Another distortion occurs with the nature of the ‘client group’. It strikes me that any CAM research done in a naturalistic setting should involve in-depth interviewing of the receptionist. In our Hove clinic the receptionist, Tracey, swears she has never encountered such a demanding group of patients who consistently fail to make their appointments. Tracey has the social skills of a Bodhisattva but she has been seen needling voodoo dolls after a particularly gruelling endometriosis encounter. Maybe this is the downside of free treatments but it is a problem for gathering data, doing blood tests at the right time, and it is another distortion to the clinical practice that inspired the research in the first place.
In a nutshell: rather than researching what goes on in daily practice I am now researching what goes on during a research trial; an obvious but important difference.
The Promised Land…
The trial needs to be completed by October 2008. After that I will still need to see and treat all the women in the placebo arm of the trial, analyse and write up all the data so the end of the quest is still a distant promise. This trial is a feasibility study and in a way it cannot fail. Is it feasible to subject individualised Chinese herbal decoctions to a rigorous double-blind RCT? In a word, yes. Is it the best way to evaluate what we do in our day-to-day practice? I’m not so sure. The lens of research distorts what we do, to whom we do it, and how we measure our results. It is a laborious, expensive, time-consuming, and frequently maddening process that demands a kind of hangdog stubbornness. At the end of the day is it worth it?
At this point in time my answer is a qualified yes. In many ways the clinical trial I have described is breaking new ground. The methodology is unique, the mapping of the bureaucratic pathways is pioneering and the learning curve has been steep and painful but useful. I think/hope that future CHM research in the UK will learn from and improve on my own and other attempts to establish a research culture within our field. It should become easier to do research and it is better that we own the research process and try and bend the methodology to reflect our clinical practice as best we can. CHM in particular needs to prove effective benefits to counter the damaging charge of possible risk.
I am definitely saddle-sore, the shining armour and romance of the quest has long since gone, but it’s still part of a long and necessary struggle to improve our understanding of CM, enhance our treatment, and improve our accessibility to the general public.
I think Sir Gawain would have approved…
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Flower, A., Lewith, G.T., Little, P. Seeking an oracle: using the Delphi process to develop practice guidelines for the treatment of endometriosis with Chinese herbal medicine. J Altern Complement Med. 2007 Nov;13(9):969-76.
Giudice, L. C., Kao, L. C. Endometriosis. Lancet 2004 vol 364 pp 1789-1799.
Sheehan, M. P., Atherton, D. J. A controlled trial of traditional Chinese medicinal plants in widespread non-exudative eczema. British Journal of Dermatology 1992; 126, 179-184.
Sutton, C., Ewen, S., Whitelaw, N., Haines, P. (1997). Follow-up on a randomized controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal to moderate endometriosis. Fertility and Sterility 1997;68 (6):1070-1074.
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Xie, P. (2006) In: Annals of Traditional Chinese Medicine – Vol 2 Current Review of Chinese Medicine: Quality Control of Herbs and Herbal Material (eds.) Leung, P. C., Fong, H., Xue, C. C. World Scientific Publishing, Singapore pp 6-7.