A DOUBLE-BLINDED RANDOMIZED CONTROLLED TRIAL ON THE EFFECT OF DISTANT REIKI ON PAIN AFTER NON-EMERGENCY CEASEAREAN SECTION AND
THE EFFECT OF CYP2D6 VARIATION ON CODEINE ANALGESIA
by
Sondra vanderVaart
A thesis submitted in conformity with the requirements
for the degree of Doctor of Philosophy
Graduate Department of Pharmaceutical Sciences
Leslie Dan Faculty of Pharmacy
University of Toronto
© Copyright by Sondra vanderVaart (2011)
ii
A Double-Blinded Randomized Controlled Trial On The Effect Of Distant Reiki On Pain After Non-Emergency Ceasearean Section And The Effect of CYP2D6 Variation On
Codeine Analgesia
Doctor of Philosophy, 2011
Sondra vanderVaart
Graduate School of Pharmaceutical Sciences
University of Toronto
Abstract
Codeine-containing medication is commonly used for pain after c-section. In most people,
10% of codeine is biotransformed into morphine by the Cytochrome P450 enzyme 2D6
(CYP2D6). Individuals who convert up to 50 fold more codeine into morphine, ultrarapid
metaboizers, are at a greater risk for adverse effects. Conversely poor metabolizers, individuals
who convert almost no codeine into morphine, are at risk for untreated pain. The
pharmacodynamic relationship between codeine-analgesia and CYP2D6 genotype is studied for
possible development of a titration model. To minimize these treatment risks, alternatives to
opioids are sought. Reiki, an ancient Japanese form of healing used to treat pain and depression,
has not been systematically reviewed for its efficacy in treating pain.
My systematic review of Reiki literature (n=12) showed that while most trials yielded a
positive result on primary outcomes, all existing Reiki studies lacked in one of the three key
areas of proper patient allocation concealment, randomization or blinding which can lead to the
introduction of bias. We designed a randomized controlled trial using distant Reiki for
postpartum pain, taking careful steps to control for each of those three key areas.
Eighty pregnant women scheduled for an elective c-section where recruited and randomly
allocated to one of the two arms (n=40 Reiki and n=40 control). Women were monitored in
hospital for up to three days. Visual Analogue Scores (VAS) for pain were recorded 4 times per
iii
day; and all pain medication, adverse effects and milestone recovery rates after c-section were
recorded. Blood samples were taken to determine CYP2D6 genotype.
We determined that distant Reiki did not reduce women’s pain; neither the measured pain nor
the cumulative dose of pain medication differed between groups. Moreover, rates of recovery
after c-section were also not different between the two groups. This led to the conclusion that
distant Reiki was not suitable as a primary method of controlling pain after c-section.
Our second study (n=45) looked for correlation between CYP2D6 genotype and effectiveness
of codeine analgesia. Only a small sample of the women were genetic extremes (n=2 poor
metabolizers and n=3 ultrarapid metabolizers), while most were, as expected, extensive or
intermediate metabolizers. An individual examination of each of these cases provided valuable
insight into patients where CYP2D6 polymorphism is clinically relevant. Two of the three
ultrarapid metabolizers stopped opioid analgesia due to adverse effects, while both poor
metabolizers complained that the codeine-containing medication was not providing analgesia
(i.e. ineffective pain treatment). Healthcare providers need to be aware of patient response to
pharmacotherapy and use this information to individualize postpartum opioid analgesia.
iv
Acknowledgments
I would like to thank my supervisor, Dr. Gideon Koren, for his continued support and
mentorship, as well as his open-mindedness in helping me to pursue this research. I would also
like to thank my supervisors, Dr. Anna Taddio, Dr. Gary Rodin, Dr. Katherine Boydell and Dr.
Bonnie Stevens for their guidance throughout my research. Thanks to Dr. Howard Berger and
the staff at St. Michael’s Hospital, all of whom made my clinical research so enjoyable. I would
like to acknowledge all of the other graduate students and colleagues at The Motherisk program
who contributed to my learning and growing.
Lastly, I would like to thank my wonderful husband and children for supporting me as I
worked on this PhD, with a special mention to my son Julian who served as my inspiration.
v
Preface
This thesis is in manuscript style and contains papers that were published or submitted for
publication in peer-reviewed scientific journals. This format has been approved by the Graduate
School of Pharmaceutical Sciences and conforms to the Guidelines for Preparation of Thesis –
School of Graduate Studies, University of Toronto.
Chapter 1 is an introduction to the thesis and provides some background and rational for the
research study. Chapter 2 is a literature review on Reiki and provides recommendations on how
to make Reiki trials stronger in terms of their evidence. It is an expansion of the individual
manuscript as it includes the rationale as to why we should study Reiki, the definition and
classification of this complementary therapy and a description of what a Reiki treatment entails.
Chapters 3 and 4 are the individual manuscripts on the effect of distant Reiki on pain and the
effect of CYP2D6 genotype on pain and codeine dose. Chapter 5 is the general discussion and
includes summaries from the research paper, contributions to knowledge and clinical
implications, strengths and weaknesses of this research as well as suggestions for future studies
that may be carried out.
vi
Contents
Acknowledgments ..................................................................................................................... iv
Preface ....................................................................................................................................... v
List of Tables ............................................................................................................................ ix
List of Figures ............................................................................................................................ x
List of Appendices..................................................................................................................... xi
1 Introduction ........................................................................................................................... 1
1.1 Codeine Use in Pregnancy .............................................................................................. 1
1.2 Reiki as an alternative method of pain relief .................................................................... 2
1.3 Statement of the Problem ................................................................................................ 2
1.4 Objectives ....................................................................................................................... 3
1.5 Research Hypotheses ...................................................................................................... 3
Chapter 2 .................................................................................................................................... 4
2 Literature Review of Reiki ..................................................................................................... 5
2.1 Author contributions ....................................................................................................... 5
2.2 Abstract .......................................................................................................................... 6
2.3 Introduction .................................................................................................................... 7
2.3.1 Traditional Reiki treatments ................................................................................ 9
2.3.2 Distant Reiki Treatments ................................................................................... 10
2.4 Methods ........................................................................................................................ 10
2.4.1 Search Terms .................................................................................................... 10
2.4.2 Study Selection and Data Extraction .................................................................. 11
2.4.3 Quality Assessment ........................................................................................... 12
2.5 Results .......................................................................................................................... 16
vii
2.5.1 Jadad Methodological Quality – Findings .......................................................... 21
2.6 Discussion .................................................................................................................... 25
2.7 Conclusion and Hypothesis ........................................................................................... 28
3 Distant Reiki and Pain ......................................................................................................... 30
3.1 Author’s Contributions ................................................................................................. 30
3.2 Abstract ........................................................................................................................ 31
3.3 Introduction .................................................................................................................. 32
3.4 Methods ........................................................................................................................ 34
3.4.1 Study Design ..................................................................................................... 34
3.4.2 Participants........................................................................................................ 35
3.4.3 Intervention ....................................................................................................... 35
3.4.4 Cesarean Section, anesthesia and analgesia protocol .......................................... 36
3.4.5 Outcome Measures ............................................................................................ 37
3.4.6 Statistical Analysis ............................................................................................ 38
3.5 Results .......................................................................................................................... 40
3.6 Discussion .................................................................................................................... 45
3.7 Conclusion .................................................................................................................... 48
4 CYP2D6 variability and codeine analgesia ........................................................................... 50
4.1 Author Contribution ...................................................................................................... 50
4.2 Abstract ........................................................................................................................ 51
4.3 Introduction .................................................................................................................. 52
4.4 Materials and Methods .................................................................................................. 53
4.4.1 Patient s and Study Design ................................................................................ 53
4.4.2 Outcome Measures ............................................................................................ 54
4.4.3 Statistical Analysis ............................................................................................ 56
4.5 Results .......................................................................................................................... 57
viii
4.5.1 Relationship of genotype to pain outcomes ........................................................ 63
4.5.2 Individual analysis of extreme genotypes .......................................................... 63
4.6 Discussion .................................................................................................................... 66
4.7 Conclusions .................................................................................................................. 68
5 General Discussion .............................................................................................................. 70
5.1 Summary ...................................................................................................................... 70
5.2 Strengths and weaknesses ............................................................................................. 74
5.3 Conclusions .................................................................................................................. 75
5.4 Implications for future work.......................................................................................... 75
6 References ........................................................................................................................... 78
7 List of Publications .............................................................................................................. 90
8 Appendices .......................................................................................................................... 92
ix
List of Tables
Table 1: Original CONSORT criteria for Herbal Interventions ................................................. 15
Table 2: Study scores................................................................................................................ 17
Table 3: Study Type, Interventions, Outcomes and Reporting Quality based on a Modified
CONSORT-Based Checklist ..................................................................................................... 18
Table 4: Jadad Scores ............................................................................................................... 22
Table 5: Summary of studies .................................................................................................... 23
Table 6: Patient characteristics................................................................................................. 43
Table 7: Outcomes................................................................................................................... 44
Table 8: Patient Characteristics ................................................................................................. 59
Table 9: CYP2D6 allele and genotype frequencies, activity scores and predicted phenotypes ... 60
Table 10: Pain scores, medication dosing and milestone recovery times ................................... 61
x
List of Figures
Figure 1: Flow diagram of selection process ............................................................................. 12
Figure 2: Visual Analogue Scores for pain. …………………………………………………….40
Figure 3: Patient recruitment .................................................................................................... 41
Figure 4: Individual analyses .................................................................................................... 65
xi
List of Appendices
Appendix 1: Data collection forms ........................................................................................... 92
Appendix 2: St. Michael’s Hospital documentation ................................................................. 96
Appendix 3: Published Studies………………………………………………………………101
xii
Chapter 1
1
1 Introduction
1.1 Codeine Use in Pregnancy
Approximately 25% of all babies in North America are delivered via caesarean section (1);
alleviating pain early after c-section is important as studies have shown that post operative pain, in
addition to maternal suffering, negatively affects a mother’s ability to care for and breastfeed her
infant (2). To alleviate post operative pain, opioids are commonly used after c-section (3). Codeine, a
commonly used opioid for that purpose, is a pro-drug, biotransformed through o-demythlatione into
morphine. This process is catalyzed by the highly polymorphic cytochrome P450 enzyme 2D6
(CYP2D6), which is the single most important factor in determining the efficacy of codeine analgesia
in adults. In most people, 10% of ingested codeine is converted into morphine; however, this
percentage can increase up to 50-fold in individuals who have multiple copies of the CYP2D6 allele
(ultra metabolizers); while those who lack CYP2D6 activity (non-metabolizers) have very little
analgesic effect from codeine (4).
Morphine passes into breast milk. In 2005, a published study alerted the medical community to a
case in which a full term breast-fed baby died from a morphine overdose as a result of his mother
taking Tylenol #3 with codeine to manage her pain; the mother was a CYP2D6 ultrarapid metabolizer
and had converted more than 10% of codeine into morphine (5, 6). Maternal breast milk is considered
the optimal nutrition for infants, and the American Academy of Pediatrics recommends exclusive
breastfeeding for the first six months of life (7). To ensure that all mothers who are recovering from
c-sections and wish to breastfeed are able to do so safely, alternatives to opioids are sought. In the
event that codeine-containing medication is used for analgesia, it would be ideal if one could model
2
the codeine dose-analgesic effect relationship for the various groups of CYP2D6 metabolizers, so
healthcare providers could titrate a women’s codeine dose maximizing analgesic effect and
minimizing adverse effects.
1.2 Reiki as an alternative method of pain relief
The National Center for Complementary and Alternative Medicine (NCCAM) classifies Reiki as
an energy medicine (8). This complementary and alternative medicine (CAM) therapy, used to
alleviate pain and depression (9), is administered by a Reiki practitioner who maintains a meditative
presence and sends healing energy through their hands to a patient.
Reiki is used by over 1.5 million Americans and its popularity is growing (10). This is reflected in
the popular media by the definition of Reiki by Dr. Oz, host of the Dr. Oz Show and frequent Oprah
guest, as his “ultimate CAM therapy for 2010”(10). Several studies have suggested a reduction in pain
with the use of Reiki (11),(12)(13)(14); furthermore, one of these studies found that women who
received Reiki after hysterectomy reported less pain and requested fewer analgesics (11). However,
while it is commonly practiced, no systematic review of its effectiveness has been conducted.
1.3 Statement of the Problem
Given the risk of morphine exposure in neonates, there is a need for alternate pain control
treatments for breastfeeding mothers. Many CAM modalities are available and utilized during
pregnancy but without scientifically rigorous data to support their use (15). This thesis will
systematically review the existing Reiki literature and detail the methods and results of a randomized
controlled trial to examine whether Reiki is efficacious as a primary means of controlling pain for
3
women post caesarean section. In addition, for mothers who take codeine after c-section, we will
study the relationship between CYP2D6 genotype and codeine analgesia.
1.4 Objectives
The decision to avoid codeine and use Reiki as a primary means of analgesia should be based on
scientific evidence of effectiveness. This research sought to evaluate whether sufficient evidence
exists to support the analgesic effects of Reiki and to model codeine analgesia in various groups of
CYP2D6 genotyped women. The specific objectives of this thesis are the following:
1. To determine if the existing scientific literature provides sufficient evidence that Reiki
is effective for pain reduction.
2. If sufficient evidence does not exist, to conduct a randomized controlled trial
evaluating distant Reiki for the management of pain after caesarean section.
3. To determine the pharmacodynamic relationship between CYP2D6 genotype and
codeine analgesia.
1.5 Research Hypotheses
The hypotheses tested in this thesis are the following:
1. Reiki studies are of poor quality and strong evidence of their effectiveness is lacking.
2. Distant Reiki is effective in reducing pain after elective caesarean section.
3. A positive relationship exists between CYP2D6 genotype and codeine analgesia such
that a pharmacodymanic model can be developed.
4
Chapter 2
5
2 Literature Review of Reiki
The study is published and referenced as: vanderVaart, S., Gijsen, V.M.G.J., de Wildt, S.N.,
Koren, G. A systematic review of the therapeutic effects of reiki. Journal of Alternative and
Complementary Medicine 2009; 15; 1157-69.
.
2.1 Author contributions
Sondra vanderVaart, Violette MGJ Gijsen, Saskia N de Wildt and Gideon Koren designed the
study. Sondra vanderVaart and Violette MGJ Gijsen acquired and analyzed the data. Sondra
vanderVaart drafted the article. All authors interpreted and revised the manuscript for intellectual
content.
6
2.2 Abstract
Introduction: Reiki is an ancient form of Japanese healing. While this healing method is widely used
for a variety of psychological and physical symptoms, evidence of its effectiveness is scarce and
conflicting. The purpose of this systematic review was to try to evaluate whether Reiki produces a
significant treatment effect. Methods: Studies were identified using an electronic search of Medline,
EMBASE, Cochrane Library and Google Scholar. Quality of reporting was evaluated using (1) the
modified CONSORT Criteria for Herbal Interventions and (2) the Jadad Quality score. Data
Extraction: Two researchers selected articles based on the following features: placebo or other
adequate control (i.e. sham, cross-over), clinical investigation on humans, intervention using a Reiki
Practitioner and published in English. They independently extracted data on study design, inclusion
criteria, type of control, sample size, result and nature of outcome measures. Results: The modified
CONSORT Criteria indicated that all 12 trials meeting the inclusion criteria were lacking in at least
one of the three key areas of randomization, blinding and accountability of all patients, indicating a
low quality of reporting. Nine of the 12 trials detected a significant therapeutic effect of the Reiki
intervention; however, using the Jadad Quality score, 11 of the 12 studies ranked “poor”.
Conclusions: The serious methodological and reporting limitations of limited existing Reiki studies
preclude a definitive conclusion on its effectiveness. High quality randomized controlled trials are
needed to address the effectiveness of Reiki over placebo.
7
2.3 Introduction
There is growing interest in complementary and alternative medicine (CAM). The National Center
for Complementary and Alternative Medicine (NCCAM) describes CAM as “a group of diverse
medical and healthcare systems, practices and products that are currently not part of conventional
medicine (8). Canadians spent an estimated $5.6 billion dollars out of pocket for CAM expenditures
in the twelve months ending June 2006 compared to almost $2.8 billion in 1997 (16). Both Gordon
(17) and Schiller (18) suggest that the awareness, use and integration of CAM are beginning to shift
from the marginal fringes to the mainstream of care (19).
An estimated 1.5 million Americans use Reiki with many more world-wide (20).
Reiki is a therapy that claims to provide healing energy to recharge and rebalance the human
energy fields, creating optimal conditions needed by the body’s natural healing system (19). Reiki,
which is the Japanese term for “universal life energy”, is believed to have originated thousands of
years ago in Tibet and was re-established in the 1800s after having been forgotten, by Dr. Mikao Usui,
a Japanese Monk.
Energy based healing interventions have been found throughout history:
Hippocrates referenced the “biofield” of energy flow from people’s hands,
The Indian Chakra system is based on energy centers in the body, and
Eastern energy practices like QiGong rely on the breath to balance the body’s energy
field
Classified by the National Center for Complementary and Alternative Medicine (NCCAM) as a
biofield energy therapy, studies have suggested that Reiki reduces anxiety and depression and
increases relaxation and comfort (19, 21). Also, Reiki is now widely used, mostly outside of
8
mainstream medicine, to relieve pain, especially postoperative pain and to facilitate patient recovery.
Reiki practice is administered through a gentle laying on of hands, or in absentia (i.e. distant Reiki
where the Reiki practitioner is not present). Both types of practice are based on the assumption that
the Reiki practitioner maintains a meditative presence and allows the Reiki energy to flow to where
the patient needs it, in a non-directed and non-diagnostic manner (19).
Reiki is typically taught in three levels (sometimes four, as the third level can be broken into part I
and part II) (22). The focus of Reiki Level I is on recovering the natural healing abilities of the body.
Reiki Level II teaches a deeper understanding of the energetic flow and introduces symbols to aid in
treatment efficacy. The third level, Reiki Master, is almost completely focused on the inner spiritual
development of the Reiki practitioner and most of the practices at this level concern themselves with
the development of spiritual consciousness. Reiki Master training also focuses on the development of
the skills needed to teach this work to other Reiki students. A necessary step in all levels is an
“attunement” by a Reiki Master. The attunement (or initiation) process allows the Reiki energy to
flow from the Reiki practitioner’s hands to the patient. Without an attunement from a Reiki Master, a
person cannot be said to be practicing Reiki, even if they learn the technical aspects of where to put
their hands.
Energy-based healing encompasses a belief in a greater healing force and is inherent in many
cultures. For example, healing approaches of the indigenous people of China, Tibet, Africa, Native
America and India are thought to work because of the members’ belief in the expectation of healing
(23). However, these cultures maintain that healing, like illness, is not limited to those who believe in
it, and that an illness is the result of a blockage in one’s energy field. By introducing an energy-based
intervention, the energy blockage is believed to be removed and this is believed to serve to rebalance
the body’s energy field which in turn re-balances the physical body (23).
9
If there is more to healing than belief, these effects should be able to be measured. Current
scientific thinking indicates that the best way to measure the true effect of a biomedical intervention
requires proper randomization, control, blinding and concealment. These processes decrease the
likelihood of bias and ensure internal study validity to help determine whether healing claims are
more than belief (23). While Reiki itself is not a biomedical intervention, it is used in the treatment of
a variety of psychological and physical symptoms, which might otherwise be treated with biomedical
interventions (e.g. pharmaceutical substances). In this regard, its efficacy needs to be proved.
Reiki proposes to heal the whole patient, and is not directed solely to cure/relieve a single ailment.
This whole system healing may require advanced techniques, such as nested qualitative research
within an RCT to measure its effectiveness (24). Given the complexity of measuring such effects,
well-designed, well-executed clinical trials are a pre-requisite, and any intentional deviations from the
accepted gold-standard RCT should be documented and explained.
Presently, despite increased interest and awareness, the results of specific studies on Reiki are
inconclusive. The objectives of this systematic review were to: 1) evaluate the quality of reporting of
clinical trials using Reiki as the treatment modality and 2) evaluate the quality of existing evidence on
the efficacy of Reiki in humans.
2.3.1 Traditional Reiki treatments
In a traditional Reiki session, patients sit or lie down, fully clothed, while the healer holds their
hands on or slightly above the patient; there is no pressure on the body. The Reiki practitioner
maintains a meditative presence while they direct healing energy through their hands to the patient’s
10
body. The ease of use of Reiki is based on hand positions; the traditional Reiki hand positions cover
the seven major chakras and many acupuncture points.
2.3.2 Distant Reiki Treatments
A distant Reiki treatment is like distant prayer, in that the practitioners are thinking of their
patients from a distance. In distant Reiki, Reiki practitioners first undertake a specific protocol which
allows them to send the healing energy to the distant patient. Secondly, practitioners mentally ask the
person who is absent if he or she consents to treatment. Lastly, if practitioners do not hear a response
or if they hear “yes” in their head, they follow the same procedure as for traditional Reiki but they
place their hands on a substitute (e.g., pillow) for the person being treated; if they hear “no”, the
session ends immediately.
2.4 Methods
A review of the scientific literature was conducted to assess the scientific evidence supporting the
use of Reiki, especially for reducing pain.
2.4.1 Search Terms
Studies were identified by an electronic search of the Medline, EMBASE and the Cochrane
Library databases from their inception to the end of December 2008. The following search terms
(Figure 1) were employed in Medline: Reiki, Reiki AND randomized controlled trial, Reiki AND
clinical trial, Reiki AND clinical, Reiki AND trial. In EMBASE the following terms were used:
Reiki.mp, Reiki AND randomized controlled trial, Reiki AND clinical trial. We employed the
additional search terms to eliminate all the studies which were not clinical trials. We also used
11
Google and Google Scholar to identify any articles or other publications that may have been missed.
The reference lists of the selected articles were checked for additional studies that were not originally
found in the search. In addition, given Reiki’s Japanese origins, Medline and EMBASE were searched
for Reiki studies published in Japanese, however none were found.
2.4.2 Study Selection and Data Extraction
Two researchers (SV, VG) independently reviewed the list of unique articles for studies that fit the
inclusion criteria (see below). The researchers were not blinded to the report name or author. Studies
were selected based on the following inclusion criteria:
(1) Presence of test group and control group (using either placebo, cross-over, sham or usual care)
(2) Human subjects
(3) A Reiki healer being responsible for the intervention
(4) English language
(5) Studies published up to December 2008
Uncertainties over study inclusion were discussed between the researchers and resolved through
consensus.
12
Figure 1: Flow diagram of selection process
2.4.3 Quality Assessment
Each study was assessed on whether or not they reported a statistically significant outcome
measure for the Reiki intervention group. Each study was evaluated and counted only once regardless
of how many statistically significant outcome measures they reported. The raw count was used to
determine the percentage of studies yielding a statistically significant outcome.
We evaluated the accepted studies using a modified CONSORT (Consolidated Standards of
Reporting Trials) Criteria for Herbal Interventions (25). The original CONSORT was developed by a
13
group of scientists and editors to improve the quality of reporting of randomized controlled trials
(RCTs) (26). The CONSORT for Herbal Interventions was developed to aid editors and reviewers in
assessing the internal/external validity and reproducibility of herbal medicine trials, allowing an
accurate assessment of safety and efficacy (25). The authors chose the CONSORT for Herbal
Interventions because it specifically breaks out important details about the Intervention, which adds
important information about the Reiki trials. For example the CONSORT for HI specifically details:
(1) Dosage and Frequency – interpreted as - how long did the Reiki session last, and how many Reiki
sessions were given; (2) Practitioner - what is the level of training of the Reiki Practitioner as well as
the number of years of experience. (3) Placebo or Control - Reiki is usually administered by having a
person present in a room with a patient (except not in the case of distant Reiki). Reiki placebo is
important in determining whether the patients and assessors were blinded.
One researcher (SV) modified the herbal dosage components of the CONSORT for Herbal
Intervention (HI), to reflect the Reiki practitioner as the intervention instead of the herb (see Table 3
for Original CONSORT for Herbal Interventions and Table 4 for modified CONSORT for Herbal
Interventions).
For each CONSORT criterion the two researchers independently assessed whether the reporting
was adequate or not and scored the criterion as: Y (yes), N (no), P (partial) or NA (not applicable).
We identified items which were adequately or not adequately reported according to the CONSORT
definition of what is required for each item.
We considered the percentage of affirmative answers as the raw score for the internal validity. A
percentage calculation was used to determine the proportion of CONSORT criteria that are adequately
addressed. Items that were rated as not applicable (NA) were excluded from the analysis.
14
To assess the methodological quality of existing Reiki studies, we used the Jadad score. The Jadad
Score is the method most authors use to assess methodological quality (27). This validated score
ranges between 0-5. Studies are scored according to the presence of the three key methodological
features of randomization, blinding and accountability of all patients, including withdrawals
(essentially subsets of the greater CONSORT criteria). Criteria are given a “0” or “1” score based on
the absence or presence of the criteria. Scores are interpreted as: 0-2: poor methodological quality; 3-
4 good methodological quality and 5 excellent methodological quality (28).
15
Table 1: Original CONSORT criteria for Herbal Interventions
Consort
Number CONSORT criteria Definition
Title and Abstract
1 word "random" or "randomization" used Word 'random' or 'randomized' mentioned
Introduction
2 Background (nature, scope, severity of problem) Nature, scope and severi ty of problem
Methods
3a Participants (eligibility) El igibi l i ty cri teria for participants (must include exclus ion cri teria)
3b Participants (setting and locations) Settings and locations of participant interventions
4a Intervention - Herbal Medicine Product Name Latin bionomial name
4b Intervention - Characteristics of Herbal Product Type of product, concentration, method of authenticating raw product
4c Intervention - Dosage Description of type and frequency of reiki intervention
4d Intervention - Qualitative Testing Product's chemica l fingerprint and who performed the analys is
4e Intervention - Placebo/control Rationale for type of control/placebo used
4e Intervention - practitioner Description of practi tioner: tra ining and practice level and years of experience
5 Primary and Secondary Objectives defined Speci fic objectives and hypothes is
6 Outcomes Clearly defined primary and secondary outcome measures
6b Quality Enhancement (if applicable) If appl icable, methods used to enhance the qual i ty of measurements (eg. Multiple observers , tra ining of assessors )
7 Sample Size determination How sample s ize was determined
7b Interim analysis and stopping rules (if applicable) If appl icable, explanation of interim results and s topping rules
8 Randomization Seq. Allocation Method used to generate the random sequence
8b Details of restriction (if applicable) If appl icable, deta i l s of restriction
9 Allocation Concealment Method used to implement the random al location sequence (eg. Numbered conta iners , centra l telephone)
10 Who generated the allocation sequence? Who generated the a l location concealment
10b Who enrolled the patients? Who enrol led patients
10c Who assigned the patents to the groups? Who ass igned patients to groups
11 Blinding (were participants and therapists blinded?)Whether or not participants and therapis ts were bl inded
11b Blinding( were the assessors blinded?) Whether or not assessors were bl inded
11c How was success of blinding evaluated (if applicable)If appl icable, how success ful was bl inding
12 Statistical methods Statis tica l methods used to compare groups for primary outcome(s )
Results
13 Participant Flow
Flow of participants through each s tage (diagram recommended). For each group report number of participants
randomly ass igned, receiving intended treatment, completing s tudy protocol and analyzed for primary outcome.
13b Report of study violations (if applicable) Report s tudy violations with reasons
14 Recruitment Dates defining the periods of recrui tment and fol low-up
15 Baseline data Basel ine demographic and cl inica l characteris tics of each group (including concomitant medication, CAM use, etc)
16 Numbers Analyzed No. of participants in each group;
16b Was it intention-to-treat analysis? State whether analys is was "intention-to-treat"; s tate numbers in absolute (eg. 10/20).
17 Outcomes and Estimations State summary of effect for each group and effect s ize
17b Precision of the effect size State precis ion of the effect (ie. 95% CI)
18 If applicable, ancillary analysis stated in protocol?Address multipl ici ty by s tating any other analyses performed including sub-group analyses and adjusted analyses
19 Adverse Events (if applicable) State any adverse events or s ide effects in each intervention group
Discussion
20 Interpretation
Interpretation of results taking into account s tudy hypothes is , source of potentia l bias and dangers associated
with multipl ici ty of analyses
21 Generalizability External va l idi ty of tria l results ; expla in how treatment offered is s imi lar in sel f-care/practice
22 Overall evidence General interpretation of results in the context of current evidence
16
2.5 Results
A total of 485 unique articles were identified using Reiki as the only search term. To limit the
articles to clinical trials only, we employed additional search terms as described above. As a result
study count was reduced to 76 (Figure 1). The majority of these studies were either (a) small studies
with no control arm, (b) descriptive case studies where researchers described a single patient Reiki
intervention and/or recounted its history or (c) studies using Therapeutic Touch (a similar but distinct
therapy) and thus were excluded. Thirteen studies fulfilled the aforementioned inclusion criteria. One
study (29) was removed from the analysis because the intervention included two different types of
practitioners (Reiki and Le Shan) and thus the results of the Reiki practitioner could not be isolated.
This left a total of twelve studies to analyze.
Since four of the studies did not indicate the level of experience and/or the number of years of
experience of the Reiki practitioner, the researchers attempted to contact the primary authors to obtain
this information. The researchers were successful in contacting two of the authors (30), (31) ; and
unsuccessful with authors for two of the studies (32, 33).
All of the studies differed in their studied populations and outcome measures. Of the 12 studies, 3
studies administered Reiki for physiological symptoms such as stroke recovery, seizure rate and heart
rate and 9 studies administered Reiki for psychological symptoms such as anxiety and depression. A
total of 31 different outcome measures were evaluated in the trials, none of which were used in more
than 3 studies (Table 1). Hence, the heterogeneity of the studies’ outcomes precluded a formal meta-
analysis.
17
Table 2: Study scores
Consort
Number CONSORT criteria 30 36 34 12 11 32 33 13 37 14 31 35 Yes No Partly NA
Title and Abstract
1 word "random" or "randomization" used y n y n na na y y n y n y 6 4 0 2
Introduction
2 Background (nature, scope, severity of problem) y y y p y p y y p y p p 7 0 5 0
Methods
3a Participants (eligibility) y y y y y y y y y y p y 11 0 1 0
3b Participants (setting and locations) p y n p p y p p y p n p 3 2 7 0
4c Intervention -dosage regimen y y y y y p y y y y p y 10 0 2 0
4e Intervention -control group y y y y y y y y p y y y 11 0 1 0
4f Intervention -practitioner n y y p y n p y y y n y 7 3 2 0
5 Primary and Secondary Objectives defined y y y y y y y y y y y y 12 0 0 0
6 Outcomes p y p y n y y y y p y y 8 1 3 0
6bQuality Enhancement of the Outcome
Measurement y y y y y y y y y y y y 12 0 0 0
7 Sample Size determination n y n y n n y y n n n n 4 8 0 0
7b Interim analysis and stopping rules (if applic.) na na na na na na na na na na na na 0 0 0 12
8 Randomization Seq. Allocation n n n y y n y n n n n y 4 8 0 0
8b Details of restriction (if applicable) na na na na na na y na na y na y 3 0 0 9
9 Allocation Concealment n n p p n n y n n n n y 2 8 2 0
10 Who generated the allocation sequence? n n n n y n y n n n n y 3 9 0 0
10b Who enrolled the patients? n n n y y n y n n n n y 4 8 0 0
10c Who assigned the patents to the groups? n n n n y n n n n n n n 1 11 0 0
11 Blinding (were participants blinded?) y y y n n n n n n y y y 6 6 0 0
11b Blinding( were the assessors blinded?) n n y p n n y n n n n y 3 8 1 0
11c Was success of blinding evaluated? n y n na na na na na na n n n 1 5 0 6
12 Statistical methods y p y y n y y y y y y y 10 1 1 0
Results
13 Participant Flow n p n p n n y y p y p p 3 4 5 0
13b Report of study violations (if applicable) na na na p na n y y n p y y 4 2 2 4
14 Recruitment n n n p n n y p n y n y 3 7 2 0
15 Demographic and clinical characteristics y y p y n y y y p y y y 9 1 2 0
16 No. of participants in each group? p y y y y y y y y y y y 11 0 1 0
16b Was it intention-to-treat analysis? n y n n n n y y y y n n 5 7 0 0
17Effect size for each group for each outcome
measure p p y p y y y y p p p y 6 0 6 0
17b Precision of the effect size n p p p p n y p p p p p 1 2 9 0
18 If applic., ancillary analysis stated in protocol? na na na na na na na na na y na p 1 0 1 10
19 Adverse Events (if applicable) na na na na na na n na n n n n 0 5 0 7
Discussion
20 Discussion/Interpretation p y y y y y p y n y p y 8 1 3 0
21 Generalizability p y y y y n y y n y p y 8 2 2 0
22 Overall evidence n p n y p y y n n y n p 4 5 3 0
sum 191 118 61 50
percent of applicable CONSORT criteria (n=370) 52% 32% 16%
SUM of StudiesIndividual Studies
18
Table 3: Study Type, Interventions, Outcomes and Reporting Quality based on a Modified
CONSORT-Based Checklist
Study
Ref.
No.
Type of
Trial*
Comparison of Intervention (Whether reiki
…) Outcome Measure
Adequately
Reported
Applicable
Criteria
30
Test/
Control
produces changes in autonomic nervous
system
Heart Rate (HR), Blood Pressure (BP), Cardiac Vagal Tone
(CVT), Cardiac Sens i tivi ty to Baroreflex (CSB) and Respiratory
Rate (RR) 10/30 (33%)
36
Test/
Control
aids in the recovery & rehabilitation in
sub-acute stroke patients
Functional Independence Measure and Depress ion (FIM),
Center for Epidemiologica l Studies- Depress ion Sca le (CES-
D) 17/30 (57%)
34 RCT reduces depression and stress
Beck Depress ion Inventory (BDI), Beck Hopelessness Sca le
(HS), Perceived Stress Sca le (PSS) 15/30 (50%)
12 RCT
reduces pain and improved quality of life
in cancer patients Visual Analogue Sca le (VAS), Analges ic Use, BP, RR, HR 15/30 (50%)
11 RCT
reduces pain and anxiety in women with
hysterectomies State-Tra i t Anxiety Inventory (STAI), VAS 15/28 (54%)
32
Test/
Control
changes the isoprenioid pathway in
seizure patients HMG Co-A reductase activi ty, serum digoxin level 12/29 (41%)
33 RCT
reduces anxiety and depression in
women undergoing breast biopsy STAI, CES-D, Hospita l Anxiety - Depress ion Sca le (HADS) 27/32 (84%)
13
Pilot
Cross
Over
reduces cancer-related fatigue in cancer
patients
Edmonton System Assessment System (ESAS); Functional
Assessment of Cancer Therapy - General (FACT-G) - Fatigue
(FACT-F) 19/30 (63%)
37
Test/
Control
improves memory and behavour
deficiencies in patients wit Alzheimer's
disease
Annotated Mini -Mental State Examination (AMMSE) and
Revised Memory and Behaviour Problems Checkl is t (RMBPC) 10/31(32%)
14 RCT
reduces pain, anxiety and depression in
chronically ill patients
General Information Questionnaire; Socia l Readjustment
Rating Sca le; McGi l l Pa in Questionnaire; BDI II; STAI; Rotter I-
E Sca le; Rosenberg Sel f-Esteem sca le; Bel ief in Personal
control Sca le 20/34 (59%)
31
Test/
Control
reduces pain and improves mobility in
patient with Painful Diabetic Neuropathy
McGi l l Pa in Questionnaire; 6 min walk test; Epidemiology of
Diabetes Intervention and Compl ications qual i ty of l i fe
Questionnaire; Wel l Being Questionnaire; Diabetes
Treatment Satis faction Questionnaire 10/32 (31%)
35
Pilot
(Test/
Control)
reduces anxiety level of women
undergoing their first amniocentesis
Sheehan Patient-Related Anxiety Sca le (SPRAS) and
Subjective Unit of Dis turbance Sca le (SUDS) 24/34 (71%)
Total 194/370 (52%)
*as determined by researchers after reviewing the study
19
CONSORT Reporting Quality - Findings
The evaluators disagreed in 33% of the evaluations with the majority of the disagreements
resulting from a difference in interpretation in what constituted partial (p) vs. full rating (y) for the
CONSORT analysis. After consensus discussions, the remaining disagreements (1%) were resolved
by a third researcher (SNW).
The 12 trials that studied a Reiki intervention in either a randomized controlled fashion or as a test
vs. control experiment are presented in Table 4. Eight of the 12 studies identified themselves as
RCTs. However upon analysis of each of the study’s text, the researchers were only able to identify 5
of the 12 (42%) publications as true RCTs. (12)(33)(11)(34)(14).
Individual total applicable CONSORT criteria varied by study (see Table 4 for an individualized
reporting of each criterion and Table 1 for a Summary of Adequately Reported Criteria by study).
Fifteen percent of the CONSORT Criteria items were not applicable for many of the trials (e.g.
Interim analyses, randomization restrictions, ancillary analyses, blinding of practitioner). Items that
were not applicable were not included in the calculations. For the group of 12 studies evaluated in the
35 item modified CONSORT checklist, over half of all items (52%) were reported adequately (Table
4). The remaining items were either not reported at all (32%) or reported partially (16%).
As a group, the 12 studies reported adequately the Introduction, the beginning part of the Methods
section (CONSORT items 3-10) and most of the Results. Other than this, all the other sections were
reported less than adequately: Methods – randomization, concealment and blinding (CONSORT
items 11-22: 39% of items reported adequately); Results (specifically Intention-to-Treat: 42%
20
adequately reported and Recruitment Dates: 25% adequately reported) and the Discussion section
(56% of items reported adequately).
For individual study reporting, a median of 52% (range 31% - 84%) of applicable criteria were
reported adequately. Assessment scores for all CONSORT criteria in the 12 trials are shown in Table
1.
Items Reported Adequately
The 12 trials adequately reported issues that are defined in the Introduction and beginning of
Methods (all Methods except for Randomization, Assignment and Blinding). These include: Reiki
historical context with supporting literature, problem definition, study objectives, participant
eligibility, description of participants and control subjects, dosage regime for intervention and
differences from control group treatment, and quality enhancements undertaken to improve outcome
measurement. Over half the studies gave details about the practitioner performing the intervention.
Select criteria from the Results and Comments section were also adequately reported. These
included: demographic and clinical characteristics of the groups, discussion and generalization of the
results. The number of patients in each group was almost always explicitly stated. The majority of
studies reported mean scores and p-values, but less than half reported confidence intervals. The
CONSORT criteria explicitly state that reporting p-values alone are not sufficient. Researchers must
report confidence intervals so that readers can easily discern the overlap between mean scores.
Items Seldom Reported Adequately
We identified major shortcomings in the reporting of the items displayed in the latter part of the
Methods section (i.e. reporting the Randomization, Assignment and Blinding). Only 4 trials (11, 12,
21
33, 35, 35) adequately detailed the randomization process. Of those four trials, only two trials (33, 35,
35) described the concealment of the allocation. For allocation concealment, we assumed that when no
data was present, allocation was not concealed. A distinction was made between the two trials (33,
35, 35) where allocation was clearly concealed and those where there is some mention of
concealment, but it is unclear whether this was achieved adequately.
Other examples of inadequate reporting: three trials (11, 33, 35, 35) detailed who generated the
allocation sequence and only one trial (11) specified who assigned the patients to their groups. Six
trials (30, 31, 34, 35, 35) implemented blinding procedures for participants but only one of them
measured the success of the blinding (36). Three trials (12, 33, 34) mention blinding assessors. One
trial (36) provided extensive background on the process and success of therapist blinding (for Reiki
Level I practitioners) but only stated “patients were blinded” for the participant description. The
CONSORT clearly states that this sentence is not enough to ensure that adequate blinding was
achieved. The researchers rated this criterion for this trial as partially (p) adequately reported. In the
other trials, masking of the participants or the therapists was not achieved due to a lack of a placebo
arm (only a test and a control group).
Eight trials identified specific primary outcome measures but of these trials only 4 studies (12, 13,
33, 36) provided a full rationale for sample-size calculation. On the basis of the reported numbers in
the whole participant flow, we inferred that an intention-to-treat analysis was present in 5 of the trials
(13, 14, 33, 36, 37). Three trials (12, 14, 35, 35) mentioned the date range of the patient recruitment.
2.5.1 Jadad Methodological Quality – Findings
Based on the Jadad scores, 11 of the 12 studies were rated as methodologically “poor” with one
study (20) rated as good. No studies were rated as “excellent” (Table 5).
22
Table 4: Jadad Scores
Item No. 30 36 34 12 11 32 33 13 37 14 31 35
1 1 0 1 0 0 0 1 1 1 1 1 1
2 0 0 0 1 1 0 1 0 0 0 0 1
3 0 1 0 0 0 0 0 0 0 0 0 0
4 0 1 1 0 0 0 0 0 0 0 0 0
5 0 1 0 1 0 0 1 1 1 0 1 0
6 0 0 0 0 0 0 0 0 0 0 0 0
7 0 -1 0 0 0 0 0 0 0 0 0 0
Total 1 2 2 2 1 0 3 2 2 1 2 2
Score interpretation:
0-2 poor
3-4 good
5+ excellent
Study Reference No.
2.5.1.1 Study Results linked to level and experience of Reiki practitioner
Of the 128 studies evaluated, 9 stated significant positive findings on at least one outcome
measure (not necessarily the primary outcome, as this often was not stated) while the other 3 studies
(36)(33)(31) showed no significant outcomes (Table 2).
Of the 3 studies which showed no significant effect of Reiki , one (36) utilized a Reiki Master and
14 Level I Reiki practitioners; one used multiple Reiki Masters (31)and the other study (33) utilized 6
Level I or II Reiki practitioners. Of the 9 studies that showed a significant positive Reiki effect, 8 used
a Reiki Master (or a Level II Reiki practitioner with more than 3 years experience). For the remaining
study (32), the researchers were not successful in their attempts to contact the author to determine the
information (i.e. level of training or years of experience of the Reiki practitioner). As far as we could
tell, no significant positive findings were found with Level I or II Reiki practitioners with less than 3
years of experience.
23
Table 5: Summary of studies
Ref
No.
Year Authors Journal Study
Hypothesis
Population and
Study Type
Outcomes Conclusion
30 2004 Mackay N,
Hansen S,
McFarlane
O.
The Journal
of Alternative
and
Complemen
tary
Medicine
Reiki
influences the
autonomic
nervous
system.
n = 45, 24
females, 21
males, aged 23-
59 years. Test
vs Control
Diastolic blood pressure response
(P<0.005) and Heart Rate changes
(P<0.005) were significantly different
between Reiki and placebo.
Reiki has some effect
on the autonomic
nervous system.
34 2004 Goldman
Shore A.
Alternative
Therapies in
Health and
Medicine
Reiki reduces
psychological
depression
and self-
perceived
stress
n = 45, age 19-
78. All in need
of treatment for
symptoms of
depression and
stress. RCT
Significant difference on the Perceived Stress
Scale (PSS) between Test 1(hands-on Reiki)
and Control (placebo group) (p>0.01; Eta
square = 0.18) and between Test 2 (remote
Reiki) and placebo group (P<0.01; Eta
square = 0.17). No significant difference
between two treatment groups. Similar
results (Test1 vs Control; Test2 vs Control)
on the Beck Depressive Index (P=0.05; Eta
square =0.9 and P=0.004; Eta square =0.18
respectively) and the Hopelessness Scale
(P=0.02; Eta square =0.12 and P=0.01; Eta
square =0.14 respectively). No significant
difference between types of treatment (hands-
on vs remote).
Hands-on Reiki and
remote Reiki can reduce
symptoms of
depression,
hopelessness, and
stress. No significant
difference between
hands-on and remote
reiki. The results were
not due to placebo
effects.
n = 15, age 20-
30 years. 8
males, 7
females. All with
refractory
seizure
disorder.
The average seizure frequency decreased
after treatment (2 per month in stead of 9 per
month; p<0.01). Increase in RBC membrane
Na+-K
+ ATPase activity (p<0.01), serum
magnesium (p<0.01) and a reduction in HMG
CoA reductase activity (p,0,01) and digoxin
synthesis (p<0.01), post-therapy.
Test vs Control:
1 control group
randomly
chosen from the
general
population of
Trivandrum city.
The concentration of serum tryptophan
(p<0.01), quinolinic acid (p<0.01) and
serotonin (p<0.01) were reduced, post-
therapy. The concentration of tyrosine
(p<0.01), dopamine (p<0.01) and
noradrenaline (p<0.01) were increased, post-
therapy.
1. Reiki
influences the
functional
recovery of
patients with
sub acute
stroke.
The main effect of the functional
independence was not significant for the
treatment group (p>0.50).
1. Reiki had little or no
effect on the functional
recovery.
2. a procedure
exists top blind
both Reiki and
sham Reiki
practitioners.
The Reiki practitioners were less confident
than the nonreiki practitioners about knowing
in which group they were initiated (p<0.06).
2. Reiki practitioners
and sham practitioners
did not differ in
experience or
sensations
12 2003 Olson K,
Hanson J,
Michaud M.
Journal of
Pain and
Symptom
Managemen
t
Reiki results in
better pain
control, less
analgesic use,
and an
improved
quality of life.
n = 24, 9 men
(average age
59.5 years) and
15 women
(average age 56
years), currently
receiving
palliative care
due to
advanced
cancer. RCT
A significant drop in pain in the standard
opioid plus Reiki group on day 1 and 4 (p=
0.035; p = 0.002, respectively). Also a
significant drop in diastolic blood pressure (p
= 0.035; p=0.082, respectively) and pulse
(p=0.019, only day 1).Quality of life
significantly improved from day 1 to 7 for the
standard opioid plus Reiki group (p=0.002).
No difference in analgesic use.
Reiki improved the
quality of life and
reduced the level of
pain, but showed no
difference in analgesic
use.
32 Reiki-like treatment
practices and
transcendental
meditation influences
seizure frequency,
biochemical pathways
related to membrane
Na+-K
+ ATPase
stimulation, and
changes in neuronal
transmission.
The Journal
of Alternative
and
Complemen
tary
Medicine
n = 50, with sub
acute ischemic
stroke. 31 male,
19 female. Test
vs Control.
2003 Kumar R,
Kurup P.
Neurology
India
Reiki-like
treatments
affect seizure
patients.
n= 22 Women
with scheduled
abdominal
hysterectomy.
RCT
At 24 hours following surgery, reports of pain
was 3.8 for the experimental and 5.4 for the
control group (t = 1.79; P = 0.04). No
difference in reports of pain at 48 and 72
hours post-surgery.
Reiki influences
postoperative pain for at
least 24 hours.
2006 Vitale AT,
O’Conner
PC.
Holistic
Nursing
Practice
Reiki has a role
as a therapy for
pain
management.
11
36 2002 Shiflett S,
Nayak S,
Bid C,
Miles P.
24
No significant difference in any of the 3
psychological distress measures (STAI, CES-
D, HADS)
Neither test nor control group showed pre-
test signs of depression or anxiety.
n=16 with
various forms of
cancer;
(women=13;
men =3);aged
33-84 (median
age of 59 years)
Significant reduction between pre-treatment
and post-seventh treatment Reiki on fatigue
(p<0.01); pain (p<0.05) and anxiety (p<0.05).
In comparison, there was no significant
difference in the rest condition. Quality of life:
Reiki had significant improvement in FACT-G
pre-test to post-test intervention (p<0.01). No
significant change in control condition.
Reiki was effective in
decreasing fatigue, pain
and anxiety in cancer
patients. Overall quality
of life improved
compared to resting
condition.
Counter-
balanced cross
over trial - each
individual
participated in
both conditions
(reiki and rest)
in random order
Washout period: After careful monitoring,
found that Reiki effect lasted for 7 days as
fatigue scores did not drop.
Reiki benefited fatigued
cancer patients for at
least 7 days
31 2007 Gillespie E,
Gillespie B,
Stevens M
Diabetes
Care
Reiki reduces
pain in diabetic
nephropathy
patients
n=207 with type
2 painful
Diabetic
Nephropathy
(PDN); Test vs
Control with 3
groups: Reiki
(n=93); mimic
Reiki (n=88);
usual care (UC)
(n=26). UC
discontinued
after 26 patients
due to poor
retention.
Significant reduction (p<0.05) between
baseline pain scores (McGill Pain Score) and
12 week pain scores for Reiki and mimic-
Reiki groups. No significant reduction for
usual care group. No significant reduction
among final pain scores for all 3 groups
(Usual care group started with lower pain
scores). Walking distance improved
significantly (p<0.05) for Reiki and mimic
Reiki groups; not for Usual Care group. All
other measures (VAS pain score; Well-Being
Questionnaire; Diabetes Treatment
Satisfaction Questionnaire) showed no
significant difference.
Reiki was no more
effective than mimic-
Reiki in decreasing
perceived pain and
improving walking
distance in patients with
PDN.
14 1998 Dressen L,
Singg S
Subtle
Energies
and Energy
Medicine
Journal
Reiki reduces
pain, anxiety
and
depression in
chronically ill
patients.
n=120 who
have been in
pain for at least
1 year; RCT with
4 groups: Reiki,
Progressive
Muscle
Relaxation;
mimic- Reiki
and no
treatment
Reiki proved significantly superior (p<0.001-
0.04) to other treatments on 10 of 12
variables measured. McGill Pain Score:
Global Pain Intensity (p<0.001); Sensory Pain
Rating Index (PRI) (p<0.03); Evaluative PRI
(p<0.001); Beck Depressive II Inventory
(p<0.0001); State Trait Anxiety Inventory (State
Anxiety, p<,0.0001), (Trait Anxiety, p<0.001);
Rosenberg Self Esteem Scale (p<0.002);
Rotter Internal-External Locus of Control
(p<0.002); Belief in Personal Control Scale
(BIPCS)(p<0.01); BIPCS-Scale C (Belief in
God)(p<0.04).
Reiki is an effective
modality for reducing
pain, depression and
anxiety. Reiki is effective
in enhancing desirable
changes in personality
(self-esteem, locus of
control). The effects of
Reiki are not due to
placebo.
37 2006 Crawford S,
Leaver W,
Mahoney S
The Journal
of Alternative
and
Complemen
tary
Medicine
Reiki results in
improved
memory and
behaviour
deficiencies in
patients with
Mild
Alzheimer's
(MA)
n=24 who
scored between
20-24 on
Annotated Mini-
Mental State
Examination
(AMMSE); Test
vs Control with
2 groups: Reiki
and no
treatment
Reiki group showed significant (p<0.05)
AMMSE post-treatment scores (improved
memory) over control; Reiki post-test scores
in the Revised Memory and Behaviour
Problems Checklist (RMBPC) were
significantly (p<0.05) improved in both
frequency and reactions over pre-test and
control group scores. Reiki group showed
significant (p<0.05-0.01) changes in memory-
related and behaviour-related questions.
Results indicate
statistically significant
(p<0.05) increases in
mental function
(AMMSE) and memory
and behaviour problems
(RMBPC) after Reiki
treatment.
35 2001 Mauro MT University of
Alberta,
Master's
Thesis
Reiki reduces a
pregnant
women's
anxiety level for
amniocentesis.
n=30 who were
>35 years of
age and 15-18
weeks pregnant
undergoing 1st
amniocentesis;
Test (n=10),
Control (n=10)
and Placebo
(n=10)
Sheehan Patient-Related Anxiety Scale
(SPRAS) and Subjective Unit of Disturbance
Scale (SUDS) scores were obtained seven
times (once before and six times after
amniocentesis). Reiki and Placebo groups
showed significant (p=0.013) reduction in
anxiety over Control group as measured by
SUDS. Significance between Reiki and
Placebo could not be established due to low
sample size.
Tentative positive results
supports a larger study
n=35 women
scheduled for
breast biopsy.
RCT
Reiki had no significant
impact. Usual coping
mechanisms were
sufficient.
33 2007 Potter P. Journal of
Holistic
Nursing
Reiki reduces
psychological
stress in
women
undergoing
breast biopsy.
Reiki reduces
pain, fatigue
and anxiety and
increases
quality of life in
cancer
patients. Reiki
effect lasts for
about 3 days.
Integrative
Cancer
Therapies
Tsang KL,
Carlson
LE, Olson
K
200713
25
2.6 Discussion
Reiki use by patients in North America is growing; however as shown by our analysis, this trend is
not supported by adequate scientific data. There are few studies available to evaluate the efficacy of
Reiki. Moreover, the few studies that are available are almost invariably of poor quality. Our analysis
shows that the most important aspects which determine study quality (randomization, blinding, and
accountability of all patients) are not well reported and neither is their absence discussed in any of the
Reiki studies, a fact that greatly diminishes the quality assessment of these trials.
We were only able to uncover 12 studies on which to perform our evaluation; these 12 studies had
31 different outcomes. This clearly shows that Reiki researchers are in “exploratory mode” in terms of
understanding the benefits of Reiki. Although most of the outcomes indicated a positive outcome, it
is quite possible that bias against the null hypothesis and the “file drawer syndrome” resulted in an
unknown number of negative trials on Reiki never being published (38). Hence to further evaluate the
validity of claimed therapeutic effects of Reiki, trials are needed with larger study populations and
better reporting quality. It is obvious that these trials should be registered with a clinical trials register
to avoid publication bias. In contrast, some researchers might argue that such studies should not be
performed at all, since the biological substrate for Reiki’s effect is unknown and plausible at best.
However, while it may be difficult to scientifically assess Reiki’s method of action with our current
technology, it is possible to determine Reiki’s efficacy. Given the increase in patient spending in
CAM, we believe it is our job as researchers to conduct good quality trials which add or refute to the
efficacy data of a given therapy.
Western medicine operates under the paradigm of evidence–based medicine. Randomized
Controlled Trials (RCTs) are considered the “golden-standard” for providing evidence on
effectiveness of bio-medical interventions (39). While Reiki itself is not a biomedical intervention, its
26
efficacy needs to be proven, in service of good science. Current literature has suggested that RCTs
alone may be limited in their ability to measure “whole person” healing which is characteristic of
CAM therapies (such as Reiki) (24). Adequate standards of reporting are necessary so that readers
can make assessments on the internal and external validity of the trial as well as properly assess the
results. The CONSORT statement was developed to aid authors in adequately reporting (and
hopefully designing) their studies. In general, current reporting of trials is not considered adequate. In
a study which looked at 253 RCTs reported in 5 leading medical journals (which have actively
embraced the CONSORT) between 2002-2003 less than 60% of the trials adequately reported on:
allocation concealment (48%), randomization implementation (55%), blinding status of participants
(40%), blinding of healthcare providers (17%) and blinding of outcome assessors (47%) (40).
Our findings are in agreement with an earlier observation that reporting of CAM trials is also poor
(41). In a project that assessed a sample of 206 RCTs of herbal medicine interventions, less than one
third adequately reported whether those administering the intervention were blinded (28%), the
methods for implementation (22%) and generation of the random allocation sequence (21%), whether
there were protocol deviations (18%) or whether outcome assessors were blinded (14%) (39).
Biofield Energy Therapies are controversial to conventional healthcare providers and policy
makers for two main reasons: (1) the dearth of rigorous scientific data which supports or refutes their
efficacy and (2) because biofields currently cannot be measured so their scientific method of action
remains questionable. While the second point may take more time to resolve, the(12) first point can be
addressed immediately, though adequate scientific reporting. In order for efficacy to be scientifically
recognized adequate reporting is required to inform readers of the purposeful deviations from
traditional RCT design so readers can judge the influence of methodological flaws on the results of
trials. In order to be accepted as true scientific evidence, adequate reporting of future Reiki RCTs or
27
mixed methods RCTs is crucial. Of the items that were not reported adequately, all of them were
reported adequately in at least one study, indicating that it is possible to report adequately.
A potentially significant finding from this study is the level of training and/or years of experience
of the Reiki practitioner seemed to be important for Reiki to be effective. A finding from the Review
of Distant Healing, suggests that healers should have at least 3 years of practice to be considered
performing optimally (42). While the author of this study was not specifically referring to Reiki
practitioners, if does make sense that a certain level of expertise improves the Reiki practitioners’
efficacy.
We exempted Reiki Masters from the “3 years of practice” criteria that we applied to Reiki
Practitioners (Level I and Level II) due to the intensive training that it takes to become a Reiki Master.
Level II training is usually only given after a student has been practicing Level I Reiki for at least
three months, though this can vary somewhat depending on the individual. Reiki Master training is
primarily intended for people who have made Reiki their life's work. Depending upon the individual,
Reiki Master level training is usually given only after a student has been practicing Level II Reiki for
at least one year and the training is quite intensive(22).
Studies that used Reiki practitioners (level I or II) with less than 3 years experience showed no
significant outcome, while in all but one of the studies which used a Reiki Master, there was a
significant difference in measured outcome in the Reiki group. The goal of Reiki is to direct healing
energy into the recipient. It has been suggested that the number of changes of Extra-Low Frequency
(ELF) Magnetic Fields coming from Reiki practitioners’ (i.e. Level I or Level II; non-Reiki Masters)
hands differs significantly than the number of changes of ELFs coming from Reiki Masters’ hands;
28
however the results of these studies have only been published in abstract and book form (43).
Although this is not a definitive test for efficacy of Reiki healers (no known test exists as far as we
know), this does suggest that there is a difference between Reiki Masters and non-Master Reiki
practitioners.
2.7 Conclusion and Hypothesis
Based on the poor quality of the Reiki studies to date, it is currently impossible to draw definitive
conclusions about the effectiveness of Reiki. A high quality RCT needs to be conducted so that
effectiveness can be determined. Given the need for alternate pain control treatments for breastfeeding
mothers, and the reduced pain observed in the women who received Reiki treatments, we aimed to
study the effect of Reiki on analgesia in women who receive a non-emergency caesarian section for
delivery. A common limitation of the current Reiki studies is the lack of blinding. To overcome this
issue, we will use distant Reiki, a technique where advanced Reiki practitioners can transfer healing
energy through intention alone, thereby ensuring the blinding of all participants, hospital staff and
researchers.
29
Chapter 3
30
3 Distant Reiki and Pain
The study is published and referenced as: vanderVaart, S., Berger, H., Tam, C.,
Goh, Y.I., Gijsen, V.M.G.J., de Wildt, S.N., Taddio, A. Koren, G. The effect of distant Reiki on
pain in women after elective Caesarean section: a double-blinded randomized controlled trial.
BMJ Open 2011; published electronically; doi 10.1136/bmjopen-2010-000021.
3.1 Author’s Contributions
Sondra vanderVaart and Gideon Koren conceived the study. Sondra vanderVaart, Howard Berger,
Violette MGJ Gijsen, Saskia N de Wildt, Anna Taddio and Gideon Koren designed the study. Sondra
vanderVaart, Y. Ingrid Goh and Carolyn Tam collected the data. Sondra vanderVaart and Gideon
Koren analyzed the data. Sondra vanderVaart drafted the manuscript. All authors contributed to data
analysis and edited the manuscript.
31
3.2 Abstract
Introduction: Approximately 25% of all babies in North America are delivered via caesarean section.
Though a common surgical procedure, c-section recovery can be painful. Opioids, specifically
codeine, are commonly used to ease pain; however, its active metabolite morphine passes into breast
milk, and may produce unwanted side effects in neonates; therefore alternatives to opioids are sought
out. Reiki is an ancient Japanese form of healing where practitioners transfer healing energy through
light touch and positive healing intention. Although 1.2 million Americans use Reiki to reduce pain
or depression, there is a lack of strong evidence supporting its effectiveness. A recent systematic
review showed existing studies to be of poor methodological quality, with the common limitation of
lack of blinding. To overcome this issue we used distant Reiki to assess its effectiveness in reducing
pain following an elective C-section. Methods: In this randomized, double blinded study, women
who underwent an elective C-section were allocated to either usual care (control, n=40) or three
distant Reiki sessions in addition to usual care (n=40). Pain was assessed using a visual analogue
scale (VAS). The primary endpoint was the Area Under the VAS-time Curve (AUC) for days 1 to 3.
Secondary measures included: proportion of women who required opioid medications & dose
consumed, rate of healing and vital signs. Results: AUC for pain was not significantly different in the
distant Reiki and control groups (mean ± SD; 212.1 ± 104.7 vs. 223.1 ± 117.8; p=0.96). There were
no significant differences in opioid consumption or rate of healing, however, the distant Reiki group
had a significantly lower heart rate (74.3 ± 8.1 bpm vs. 79.8 ±7.9 bpm, p=0.003) and blood pressure
(106.4 ± 9.7 mmHg vs. 111.9 ± 11.0 mmHg, p=0.02) post surgery. Conclusion: Distant Reiki had no
significant effect on pain following an elective C-section.
32
3.3 Introduction
Approximately 25% of all babies in North America are delivered via caesarean section (1);
alleviating pain early is important, as studies have shown that post operative pain negatively affects a
mother’s ability to care for and breastfeed her infant (2). To alleviate post operative pain, opioids, are
commonly used after c-section (3). For example, codeine, a common opioid, is a pro-drug, and it is
the relative biotransformation of codeine into morphine by the highly polymorphic cytochrome P450
enzyme 2D6 (CYP2D6) that is single most important factor determining codeine analgesia in adults.
Approximately 5-10% of ingested codeine is converted into morphine; however this percentage can
increase dramatically in individuals who have multiple copies of the CYP2D6 allele (4).
We now know that morphine passes into breast milk. In 2005, a published study alerted the
medical community to a case where a full term breast-fed baby died from a morphine overdose as a
result of his mother taking Tylenol #3 with codeine to manage her pain; the mother had several copies
of the CYP2D6 allele and had converted more than 10% of codeine into morphine (5, 6). Maternal
breast milk is considered the optimal nutrition for infants, and the American Academy of Pediatrics
recommends exclusive breastfeeding for the first six months of life (7). To ensure that all mothers
who are recovering from c-sections and wish to breastfeed are able to do so safely, alternatives to
opioids are sought.
Several complementary and alternative medicine (CAM) therapies are used to alleviate pain. In an
attempt to reduce or eliminate the need for opioid pain medication, we sought to examine the effect of
distant Reiki on pain after c-section. Reiki, an ancient Japanese form of hands-on healing, used to
33
alleviate pain and depression(9), is classified as an Energy Medicine by the National Center for
Complementary and Alternative Medicine (NCCAM)(8). Despite being an ancient Japanese practice,
Reiki is practiced by over 1.5 million Americans and its popularity is growing (20). It was promoted
by Dr. Oz, prominent cardiothoracic surgeon, host of the Dr. Oz Show and frequent Oprah guest as his
“ultimate CAM therapy for 2010”(10). However, while it is commonly practiced, there is no agreed-
upon theory for how Reiki might work and its mechanism of action is still unknown(9).
Reiki practitioners believe that they can direct healing energy through their hands to their patients.
To direct this energy, practitioners maintain a meditative presence and place their hands lightly over
the person they are treating to aid in the patient’s natural ability to heal. Reiki can be practiced either
proximally, with the patient located beside the practitioner, or distally, with the patient and
practitioner in separate locations. Both types of Reiki rely on the premise of a universal source of
healing energy which a Reiki practitioner can direct through intention.
A distant Reiki treatment is like distant prayer, in that the practitioners are thinking of their
patients from a distance. In distant Reiki, Reiki practitioners first undertake a specific protocol which
allows them to send the healing energy to the patient. Secondly, practitioners mentally ask the person
who is absent if he or she consents to treatment. Lastly, if practitioners do not hear a response or if
they hear “yes” in their head, they follow the same procedure as for traditional Reiki but they place
their hands on a substitute (eg. pillow) for the person being treated; if they hear “no”, the session ends
immediately.
Reiki may work. Several studies have found a reduction in pain when using Reiki
(11)(12)(13)(14); furthermore, one of the studies found that women who received Reiki after
hysterectomy reported less pain and requested fewer analgesics (11). While there were no studies
34
which specifically evaluated distant Reiki for pain, one study found that distant Reiki was as effective
as traditional Reiki in the management of depression and anxiety. The authors concluded that the
distant Reiki was as efficacious as traditional Reiki and the healing power of Reiki was not due to
placebo (34).
However, despite widespread and growing popularity, there is a dearth of well conducted published
scientific literature supporting or refuting Reiki’s efficacy. A recent systematic review of Reiki found that while
the vast majority of studies had positive therapeutic effects, all available studies scored poorly when
methodological quality was measured using Jadad (9); thus definitive conclusions about efficacy could not be
made. A common source of potential bias was the lack of blinding of participants and assessors when using
traditional Reiki. Patient and medical-staff blinding to treatment allocation in a clinical trial is particularly
important when the response criteria are subjective, such as alleviation of pain (44). To overcome this
limitation, we employed distant Reiki in our trial.
Given the need for alternate pain control treatments for breastfeeding mothers due to the risk of
morphine exposure in neonates, and the reduced pain observed in the women who received Reiki after
hysterectomy, our objective was to determine if distant Reiki is effective in reducing pain after
elective caesarean section, through a randomized double-blinded study.
3.4 Methods
3.4.1 Study Design
This was a double blinded randomized clinical trial. The investigators, participants, and
healthcare staff directly involved with the participants were unaware of the group assignments. The
study was approved by the research ethics board (REB) at St. Michael’s Hospital in Toronto and all
participants provided written informed consent prior to participation.
35
3.4.2 Participants
All pregnant women who were scheduled to have an elective caesarean section were approached
during a routine prenatal visit at the obstetrical clinic at St. Michael’s Hospital between September 1,
2008 and March 31, 2009. Criteria for exclusion included the following: having had previous
experience with Reiki or not planning to use standard postoperative pain medication. Women were
recruited in either English or Spanish, and those that did speak other languages were approached if
they had a translator with them, such as a husband or friend.
To ensure concealment of group assignment, the St. Michael’s Hospital research associate (SV)
enrolled participants and then contacted the research assistant (YIG) at The Hospital for Sick Children
(HSC) with the participant’s information (unique Hospital ID, date and time of c-section) for
randomization. YIG had previously computer-generated the randomized number sequence in blocks
of 4 or 6. Participants were sequentially assigned (by YIG) to the random sequence which was
securely stored and password protected on the HSC network. If the patient was assigned to the distant
Reiki group, the research assistant (YIG) contacted the Reiki Master with the participant’s
information. If the patient was in the control group, no contact was made with the Reiki Master.
3.4.3 Intervention
Participants in the control group received usual medical and nursing care during their stay
(typically 72 hours). The intervention group received usual care plus 3 distant Reiki sessions, one each
morning. The first session was administered on the morning of the caesarean section, at least 30
minutes prior to surgery, and the second and third sessions were administered on the following
mornings at approximately 8am.
A single Reiki Master located over 100 kilometres away, trained in the Usui line of Reiki and who has
been practicing Reiki for over 10 years and regularly treats clients with distant Reiki administered the distant
36
Reiki interventions. Each distant Reiki session lasted approximately 20 minutes and the Reiki Master followed
the traditional Usui Reiki protocol for distant healing(45) . The unique Hospital ID was used as the identifier
when sending distant Reiki to the participant.
3.4.4 Cesarean Section, anesthesia and analgesia protocol
All elective caesarean sections at St. Michael’s Hospital were performed using the Pfannenstiel
protocol(46). Women who underwent elective caesarean sections received a spinal anesthesia with
0.75% bupivicaine, and 15mcg fentanyl lasting 2-4 hours followed by 100 mcg of epidurally
administered morphine which typically lasts 12 hours (as per the standard protocol at St. Michael’s
Hospital). Vital signs were checked and pain and sedation scores were taken every 10 minutes for two
hours after caesarean section. Following these two hours, vital signs were taken every 12 hours on the
delivery ward.
The following analgesia protocol was administered immediately following the cesarean section:
1. Naproxen (500 mg) was given rectally and then orally every 12 hours for 48 hours.
2. For breakthrough pain: acetaminophen (300 mg) with codeine (30 mg) and caffeine (15 mg)
(Tylenol no.# 3 ®, Johnson & Johnson) , 1 - 2 tabs orally, every 4 hours, as needed;
a. patients that could not tolerate acetaminophen with codeine were given either
acetaminophen (325 mg) with oxycodone (5 mg) (Percocet®, Endo Pharmaceuticals) or
oral morphine (5 mg)
3. For mild to moderate pain: acetaminophen, 500 mg (Tylenol Extra Strength®, Johnson &
Johnson), 1 - 2 tabs orally, every 4 hours, as needed.
4. Forty-eight hours after the caesarean section, the women received a self-medication package.
This package included:
37
a. Acetaminophen, 325 mg (Tylenol®, Johnson & Johnson), 1 - 2 tabs orally, every 4 to 6
hours, as needed for mild pain control;
b. Ibuprofen, 200 mg (Advil ®, Wyeth Consumer Healthcare), 1 - 2 tabs orally, every 4 to 6
hours, as needed for moderate pain control;
c. Docusate sodium, 100 mg (Colace®, Purdue Pharma), 1 capsule orally, twice a day, as
needed for constipation;
d. Zinc sulfate monohydrate (0.5%) with hydrocortisone (0.5%) (Anusol HC Ointment®,
Pfizer Consumer Healthcare) applied to the anal area for hemorrhoids, if applicable.
5. Upon discharge, women were also given a prescription for acetaminophen 300 mg with 30 mg
codeine and 15 mg caffeine, which they could fill at their local pharmacy if required.
3.4.5 Outcome Measures
All personal patient information was de-identified by a numeric code to protect patient
confidentiality. A research associate collected baseline ethno demographic and pain history data,
while a nurse measured baseline vital signs prior to surgery and prior to first distant Reiki treatment.
All personal patient information was de-identified by a numeric code to protect patient confidentiality.
The primary endpoint for the study was the Area Under The Curve (AUC) for pain (in movement)
for days 1-3 using the Visual Analogue Scale (VAS)(47, 48), corresponding to a person’s total pain.
The VAS is a 10 cm line with an anchor at each end. Under the anchor on the left hand side is “0: no
pain”, and under the anchor on the right hand side is “10: worst pain”. A research assistant collected
two sets of pain scores three times each day (7:30-9:30am; 12noon-2:30pm; and 5:30-8:00pm). The
two sets of pain scores corresponded to: the amount of pain felt at that moment in rest, and the amount
of pain felt when moving. In addition, each morning, participants were asked to indicate the worst
level of pain felt during the night.
38
Secondary endpoints included the following ten measures: AUC for pain in motion for days 1, 2
and 3 separately; the mean VAS (in motion) from days 1-3; the mean VAS (in rest) from days 1-3; the
number of patients in need of opioid pain medication; the dose of codeine equivalent consumed per
kilogram of body weight; the number of adverse events to opioids such as constipation or itchiness;
mother’s respiratory rate, heart rate, and blood pressure (systolic and diastolic); and the time-to-first
activity (first hunger, first spontaneous voiding, first eating solid foods, first walk, etc) using a
Milestone Questionnaire. The Milestone Questionnaire was previously used on women post elective
caesarean section to evaluate their rate of healing (49). As Reiki is used not only for pain, but also to
send “healing energy to where the body needs it most”(22), this activity milestone questionnaire was
used to capture additional healing that could have taken place
3.4.6 Statistical Analysis
Reporting adhered to the CONSORT statement for reports of parallel-group randomized designs
(50). Area Under the VAS-time Curve was calculated by plotting the VAS scores on the time scale
and dividing the curve into a series of trapezoids (Figure 2). Opioid medications were converted to
codeine equivalents (60 mg oral codeine was considered equivalent to 10mg oral morphine and 6.7
mg oxycodone)(51)(52). All analyses were performed by intention-to-treat. We calculated that 40
participants per group would be required for the study to have 80% power to show a clinically
significant 25% mean reduction in pain with distant Reiki as compared to placebo. A 25% mean pain
reduction was determined a priori to be clinically relevant by our expert clinicians as the literature
concludes that 20-33% reduction is considered clinically significant (53-55). For power analysis, we
used a standard deviation in pain of 56% in the normal postoperative caesarean section population
39
(56). Baseline demographic and outcome variables were compared using the Student’s t-test, Mann-
Whitney U test or Fisher’s Exact test where appropriate. For missing data, we used the last-
observation-carried-forward method in the analysis of AUC and mean pain scores.
40
Figure 2: Visual Analogue Scores for pain in movement.
Values are mean (± sd) n=40.
3.5 Results
One hundred and thirty women were eligible for participation in this study, 47 women were
excluded (did not meet inclusion criteria, refused or did not speak English/Spanish) and 83 women
were enrolled (Figure 3). A total of 42 women were randomized to receive distant Reiki and 41
women were randomized into the control group. Three women were withdrawn from the study after
randomization: one woman (control group) was withdrawn as she suffered a severe hemorrhage
during surgery and remained in the ICU for several days, leaving researchers unable to collect her
pain score data; two participants were withdrawn from the distant Reiki group as they received
41
Figure 3: Patient recruitment
general anesthesia instead of spinal anesthesia (thus, they no longer met inclusion criteria). This left a
total of 40 women randomized into each group.
42
No patients mentally refused the distant Reiki intervention and the two groups did not differ
significantly in baseline measures or demographic characteristics (Table 6) except for birth weight of
newborns (p<0.001); differences between groups in maternal age approached significance (p=0.06).
During days 1 and 2, a total of three pain scores, which represented less than 1% of the data, were
not collected because the patients were sleeping during the time to record their level of pain; all other
data for patients were captured (pain medication consumption, physiological measures and time to
first activity) on these days. However on day 3, a total of 16 patients (20%), 8 from the distant Reiki
group and 8 from the control group, were discharged early (after 48 hours instead of after 72 hours in
hospital) resulting in 20% missing data (pain scores, pain medication consumption and time to first
activity). AUC pain data was not compared between distant Reiki and control groups for day 3 alone
due to the large amount of missing data.
No significant difference was seen between groups in the primary outcome of overall pain from
days 1-3. The mean (±SD) AUC for pain for days 1-3 in the distant Reiki and control group were
212±104 and 223±118 respectively (p = 0.96). There were no significant differences between groups
in AUC for pain for day 1 or day 2, mean VAS pain scores (in rest or in motion), use of opioids, dose
(mg/kg body weight) of opioid medication consumed or time to first activity (Table 7). The main
outcome and most secondary outcomes were normally distributed, with the notable exception of pain
medication consumption and adverse events which were not normally distributed.
43
Table 6: Patient characteristics
Reiki Control Difference p value
n=40 n=40 mean (95% CI)
Characteristics - number (%)
Maternal Age (years)
mean ± sd 35.1 ± 5 32.9 ± 6 2.2 (-0.3 to 4.7) 0.06
range 21-44 19-44
Number of Previous C-sections**
median 1 1 n/a* 0.90
range 0-3 0-3
Ethnicity*
Caucasian 19 (47.5%) 16 (40%) n/a* 0.51
Asian 12 (30%) 14 (35%) n/a*
Hispanic 3 (7.5%) 7 (17.5%) n/a*
Afro Carribbean 5 (12.5%) 3 (7.5%) n/a*
Other (Iranian) 1 (2.5%) 0 n/a*
Self-reported pain tolerance: scale (1-10)
mean ± sd 6.2 ± 2.1 6.6 ± 1.6 -0.4 (-1.2 to 0.4) 0.40
range 1-10 2-10
Weight of Mom (kg)
mean ± sd 83 ± 12.6 79 ± 15.5 4 (-2.3 to 10.3) 0.22
range 54-111 54-145
Previous Pregnancies
first time pregnancy* 4 (10%) 6 (10%)
>4 pregnancies* 3 (7.5%) 4 (10%)
mean ± sd 2.8 ± 1.2 2.6 ± 1.2 0.2 (-0.3 to 0.7) 0.40
range 1-6 1-6
Number of children living**
median 1 1 n/a* 0.94
range 0-4 0-3
Duration of cesearean section surgery (minutes)
mean ± sd 41.9 ± 11.9 45.3 ± 19.2 -34 (-10.5 to 3.7) 0.35
range 23-70 28-146
Baby APGAR scores (1-10)
1 minute (mean) ± sd 8.7 ± 0.6 8.7 ±0.7 0 (-0.3 to 0.3) 0.88
5 minutes (mean) ± sd 9.1 ± 0.5 9.3 ± 0.5 -0.2 (-0.4 to 0) 0.15
Weight of Newborn Babies (grms)
mean ± sd 3579 ± 469 3228 ± 424 351 (152 to 550) <0.001***
range 2745-5315 2625-4332
no. of babies over 4000 grms 5 (12.5%) 4 (10%)
Gestational Age of babies (weeks)
mean ± sd 38.5 ± 0.7 38.3 ± 0.6 0.2 (-0.1 to 0.5) 0.08
range 37.5-40.5 37-39.5
* P values for ethnicity and number of pregnancies was determined by Fisher's exact test.
All other comparisons were determined using an unpaired t-test unless noted;
** denotes Mann Whitney U test for non-parametric data.
Self-reported pain tolerance scores were taken before the c-section. A score of "1" was
low pain tolerance, while a score of "10" was high pain tolerance.
n/a* Not applicable to median or proportion calculations
***significance (p<0.05)
44
Table 7: Outcomes
Reiki Group Control Group Difference Signficance
⁴
Reiki Group Control Group Diffference Signficance
⁴
(n=40) (n=40) mean (95% CI) p Physiology Measures (n=40) (n=40) mean (95% CI) p
mean ± std dev² mean ± std dev² mean ± std dev² mean ± std dev²
Area Under the Curve Pain Scores (in
movement)¹ Heart Rate (per minute)
Days 1-3 combined 212.1 ± 104.7 223.1 ± 117.8 -11 (-60.6 to 38.6) 0.96 Baseline - prior to surgery 84.4 ± 9.4 84.8 ± 10.6 -0.4 (-4.9 to 4.1) 0.88
Day 1 74.2 ± 39.6 79.7 ± 42.9 -5.5 (-23.9 to 12.9) 0.55 Day 1 ( 4 hours post surgery) 74.3 ± 8.1 79.8 ± 7.9 -5.5 (-9.1 to -1.9) 0.003*3
Day 2 82.9 ± 41.5 84.5 ± 45.7 -1.6 (-21.0 to 17.8) 0.87 Difference btw Baseline to Day 1 (4 hrs post) 10 ± 11.3 4.9 ± 11.5 5.1 (0.1 to 10.2) 0.04*3
Day 1 - 8pm 79.0 ± 7.8 79.6 ± 7.7 -0.6 (-4.0 to 2.8) 0.72
Mean Pain Scores (centimenters) Day 2 - 8 am 80.5 ± 8.1 80.8 ± 7.8 -0.3 (-3.8 to 3.2) 0.84
Day 2 - 8 pm 81.3 ± 7.0 80.8 ± 6.1 0.5 (-2.4 to 3.4) 0.73
Days 1-3 (in movement) 3.1 ± 1.5 3.3 ± 1.7 -0.2 (-0.9 to 0.5) 0.61 Day 3 - 8 am 76.5 ± 8.7 77.6 ± 8.0 -1.1 (-4.8 to 2.6) 0.54
² Days 1-3 (in rest) (median, IQR) 1.1 (0.4, 1.7) 1.4 (0.6, 2.1) n/a* 0.32
⁴
*
Respiratory Rate (per min)Pain Medication Conumption (mg
codeine equivalent/kg body weight²,
⁵
)
Baseline - prior to surgery 18.3 ± 1.2 18.6 ± 0.8 -0.3 (-0.8 to 0.2) 0.19
Day 1 (median, IQR) 0.7 (0,1.4) 1.1 (0,2.0) n/a* 0.35
⁴
* Day 1 ( 4 hours post surgery) 19.0 ± 1.3 20.0 ± 4.6 -1 (-2.5 to 0.5) 0.17
Day 2 (median, IQR) 0.5 (0, 1.7) 0.6 (0, 1.5) n/a* 0.36
⁴
* Day 1 - 8pm 19.2 ± 0.9 20.0 ± 3.0 -0.8 (-1.8 to 0.2) 0.14
Days 1-3 (median, IQR) 1.7 (0, 3.12) 1.7 (0, 4.4) n/a* 0.87
⁴
* Day 2 - 8 am 19.4 ± 1.0 20.3 ± 6.5 -0.9 (3.0 to 1.2) 0.39
Day 2 - 8 pm 19.4 ± 1.0 20.1 ± 4.6 -0.7 (-2.2 to 0.8) 0.35
Patients on Opioids: number (percentage) Day 3 - 8 am 19.5 ± 1.5 20.4 ± 5.5 -0.9 (-2.7 to 0.9) 0.35
Day 1 24 (60) 26 (65) n/a* 0.56
⁴
** Diastolic Blood Pressure (mmHG)
Day 2 23 (58) 21 (53) n/a* 0.56
⁴
**
Baseline - prior to surgery 71.2± 8.6 71.3 ± 9.6 -0.1 (-4.2 to 4.0) 0.94
Number of adverse events to codeine Day 1 ( 4 hours post surgery) 66.9 ± 8.2 67.3± 8.2 -0.4 (-4.0 to 3.2) 0.82
Day 1 - 8pm 65.8± 6.9 65.9 ± 8.9 -0.1 (-3.6 to 3.4) 0.94
Day 1 (median, IQR) 0 (0,0) 0 (0,1) n/a* 0.36
⁴
* Day 2 - 8 am 64.5± 7.2 65.8 ± 8.3 -1.3 (-4.8 to 2.2) 0.43
Day 2 (median, IQR) 0 (0,0) 0 (0,0) n/a* 0.84
⁴
* Day 2 - 8 pm 66.8± 8.6 64.6 ± 7.1 2.2 (-1.3 to 5.7) 0.21
Day 3 - 8 am 64.9± 7.6 67.7 ± 7.8 -2.8 (-6.2 to 0.6) 0.09
Activity Milestone (hours)
Systolic Blood Pressure (mmHG)
Time to first hunger 15.5 ± 18.9 10.9 ± 13.0 4.6 (-2.6 to 11.8) 0.15
⁴
*
Time to first eating solid food 23.6 ± 12.1 23.9 ± 12.3 -0.3 (-5.7 to 5.1) 0.88 Baseline - prior to surgery 120.1 ± 11.7 118.1 ± 15.7 2 (-4.2 to 8.2) 0.52
Time to first flatus 19.8 ± 12.8 20.1 ± 12.4 -0.3 (-5.9 to 5.3) 0.92 Day 1 ( 4 hours post surgery) 107.8 ± 10.9 109.4 ± 12.1 -1.6 (-6.7 to 3.5) 0.54
Time to first bowel movement 57.7 ± 15.6 57.9 ± 16.7 -0.2 (-7.4 to 7.0) 0.95 Day 1 - 8pm 107.8 ± 9.7 107.3 ± 12.9 0.5 (-4.6 to 5.6) 0.85
Time to first spontaneous voiding 17.0 ± 5.5 17.7 ± 5.0 -0.7 (-3.0 to 1.6) 0.6 Day 2 - 8 am 104.0 ± 10.3 106.9 ± 10.3 -2.9 (-7.5 to 1.7) 0.21
Time to first ambulation 16.9 ± 5.3 17.2 ± 5.2 -0.3 (-2.6 to 2.0) 0.82 Day 2 - 8 pm 110.3 ± 11.3 106.0 ± 10.8 4.3 (-0.6 to 9.2) 0.08
Day 3 - 8 am 106.4 ± 9.7 111.9 ± 11.0 -5.5 (-10.1 to -0.9) 0.02*3
Difference: baseline to Day 3 @8am 13.7 ± 14.4 6.2 ± 13.3 7.5 (1.3 to 13.7) 0.02*3
¹Area Under the Curve (AUC) pain scores were calculated by taking the trapezoidal area after measuring pain scores from the VAS 10.0cm scale.
²Values are means ± standard deviation unless otherwise noted. Values were calculated based on 40 participants in each group.
³ Signficance defined as p<0.05⁴
Significance tests measured using student's t-test unless noted: Mann-Whitney test (*) or Fisher's Exact Test (**).⁵
All Opioid Medication equivalized to mg Codeine as described in the Methods section.
n/a* Not applicable to median and interquartile range
45
To determine if the two variables which varied between the two groups (baby birth weight and
mother’s age) affected the primary outcome, we performed multivariate regression analysis with three
independent variables; mother’s age, baby’s birth weight, and group allocation were regressed against
the dependent variable: AUC of pain for days1-3. Both baby’s birth weight and mother’s age were
found to be significant (p=0.013, p=0.046 respectively), while the distant Reiki group allocation was
still not significant (p=0.558).
There was a small but significant difference in heart rate on day 1, four hours after C-section (see
Figure 3 for timeline), whereby the mean (±SD) heart rate in the distant Reiki group was 74.3±8.1
bpm compared to 79.8±7.9 bpm in the control group (p = 0.003). Systolic blood pressure on day 3 at
8am was also significantly lower in the distant Reiki group (106.4±9.7 mmHg) compared to the
control group (111.9±11.0 mmHg) (p = 0.02). Otherwise, there were no significant differences
between groups in the physiological measures.
There were no significant differences in the rates of adverse events between the two groups.
3.6 Discussion
This study measured perceived pain and healing in women over their three days in hospital, while
they recovered from elective caesarean section. We found no beneficial effect of distant Reiki over
usual care for pain intensity reduction up to three days after elective caesarean section.
The lack of an observed benefit of distant Reiki for all pain outcome measures at all points in time
is in contrast to most (11-14), but not all (31), earlier Reiki pain studies. However, unlike all earlier
published studies, our study differed in two key regards: firstly, ours was the only randomized and
46
double-blinded trial. In addition to the patients not knowing their group assignment, the investigators
and outcome assessors were unaware of the intervention assignment. This suggests that the
therapeutic benefit of Reiki for pain observed in previous, non-blinded studies was a placebo effect or
that the magnitude of pain from an elective caesarean section is too great for distant Reiki to make an
impact.
Secondly, we employed distant Reiki and not traditional hands-on Reiki as our intervention. In
considering the physiological effects of Reiki, one of the basic teachings of healing with Reiki is that
we are more than our physical bodies. We also have an energy body made up of our aura (energy
fields), the chakras (energy centers) and the meridians (energy pathways.) Because Reiki healers
believe that Reiki energy is not limited by time and distance, distant Reiki healings can also be given
without the client being present (45). Reiki practitioners assert that a distant Reiki intervention works
by directing healing energy which engages the body by generating biological reactions such as pain
reduction.
It is well accepted that many constituents of living systems communicate with each other via
electromagnetic signals. A number of studies have demonstrated that weak electromagnetic fields
(EMF) are capable of eliciting in vivo and in vitro effects from different biological systems.
Endogenous electromagnetic and magnetic fields are associated with many basic physiological
processes ranging from ion binding and molecular conformation in the cell membrane to the
macroscopic mechanical properties of tissues (57-66).
In an attempt to validate energy therapies such as Reiki, researchers have been measuring classical
electromagnetic (EM) fields emitted by the body using both physical (67-70) and biologic (71)
47
detectors. However, the intensity of these fields fade rapidly with distance, and thus cannot explain
the effect of distant Reiki.
One author (72) has proposed that in addition to classical EM fields, the body generates non-
classical and quantum fields, which do not fade with distance. Several studies have shown that
quantum fields can influence neurological (73) and immunological functions (74) at the cellular level.
However, the idea that Reiki energy works through quantum fields is highly controversial and more
scientific trials need to be conducted in this area.
Another possible explanation for the lack of observed effect is the study’s sample size. Based on
our calculations, the distant Reiki would have had needed to have an effect size of 0.55; however,
based on the AUC for pain, distant Reiki had an effect size of 0.1 which is considered to be very
small. Using this effect size, a total of 2,530 patients (1,265 per group) would have been needed to
see a significant difference between groups. It is unlikely that the failure to find significant
differences is due to selection bias as only 10 women (12.5%) refused to participate in the study.
The Milestone Questionnaire which recorded time-to-first activity also showed no differences
between groups. We evaluated these responses against the measures obtained by Roseag and
colleagues (49) and found all rates of healing to be similar to their published results, except for time-
to-first eating solid foods, where our study showed an average 10 hours longer for both groups. This
could be due to the fact that St. Michael’s Hospital does not routinely allow women to eat solid foods
until after they have passed gas, regardless of whether or not they are hungry.
Despite randomization, there was a statistically significant difference between the two groups in
birth weight; differences in maternal age approached significance. Our finding that a mother’s
perceived pain decreases with maternal age is consistent with previous studies (75, 76). However, we
48
could not find any literature to support or refute the finding that larger babies born via elective c-
section caused more pain. The increase in mothers’ pain could be due to larger uteri which housed
larger babies, thereby resulting in more pain as they contracted back to normal. In addition, lifting
heavier babies post surgery could result in more pain for a recovering mother.
Heart rate taken approximately 4 hours after caesarean section and systolic blood pressure taken
on day 3 at 8am (Table 7) were significantly lower in the distant Reiki group compared to the control
group. This is consistent with three studies (12), two of which (30)(77) specifically examined the
physiological changes as a result of distant Reiki. However, given that distant Reiki’s method of
action is unknown, there is the possibility that our findings are simply due to chance given the number
of secondary measures evaluated. The small but statistically significant benefits of lower heart rate
and blood pressure levels are unlikely to be clinically significant, but may be interesting to future
researchers who are searching for a mechanism of action for distant Reiki.
The generalizability of our study may be limited given that one Reiki Master performed all of the
distant Reiki treatments; in addition given the absence of information about the mechanism of action
of distant Reiki, we chose the same dosage as a published pain trial using traditional Reiki (11).
Outcomes may differ given other Reiki practitioners and other dosage regimes.
3.7 Conclusion
In conclusion our trial showed no significant benefit of distant Reiki (administered once per day)
over usual care for pain management in the first three days after elective caesarean section. It is not
recommended as a method of primary pain relief for women undergoing elective caesarean section.
49
Chapter 4
50
4 CYP2D6 variability and codeine analgesia
The study is published and referenced as: vanderVaart, S., Berger, H., Sistonen, J., Madadi, P.,
Matok, I., Gijsen, V.M.G.J., de Wildt, S.N., Taddio, A., Ross, C.J.D., Carleton, B.C., Hayden, M. R.,
& Koren.G. CYP2D6 polymorphisms and codeine analgesia in post partum pain management: a pilot
study.
Therapeutic Drug Monitor 2011 Aug; 33(4):425-432.
4.1 Author Contribution
Sondra vanderVaart, Howard Berger, Viiolette MGJ Gijsen, Saskia Nde Wildt, Anna Taddio and
Gideon Koren designed the study. Sondra vanderVaart and Johanna Sistonen acquired the data.
Sondra vanderVaart, Johanna Sistonen, Parvaz Madadi, Ilan Matok and Gideon Koren analyzed the
data. Sondra vanderVaart drafted the article. All authors interpreted the data, revised the article
critically for important intellectual content, and approved the final version
51
4.2 Abstract
Background: Codeine, a common opioid prescribed for pain post c-section, is biotransformed by the
highly polymorphic Cytochrome P450 enzyme 2D6 (CYP2D6). Ultrarapid metabolizers (UM),
individuals with multiple active copies of CYP2D6, can biotranform up to 50% more codeine into
morphine than normal. In contrast, poor metabolizers (PM), individuals who have no active CYP2D6
genes, convert almost no codeine into morphine and as a result may take multiple doses of codeine
without attaining analgesia. Objective: To study the relationship between CYP2D6 genotype and
codeine analgesia among women recovering from c-section. Methods: Forty-five codeine-prescribed
mothers provided a blood sample for CYP2D6 genotyping and recorded their pain level 4x/day for 3
days immediately following a c-section. Codeine was used on a per needed basis. Codeine doses and
times were recorded. The relationship between CYP2D6 genotype, pain scores, need for codeine and
adverse events was studied. Theoretical morphine dose, based on CYP2D6 genotype was estimated.
Results: In this small pilot study, women at the genotypic extremes reported codeine effects
consistent with their genotype: the 2 PMs of codeine reported no analgesia as a result of taking
codeine, while two of the three UMs reported immediate pain relief from codeine, but stopped taking
it due to dizziness and constipation. Much larger numbers will be needed to study similar correlations
among extensive and intermediate metabolizers.
Conclusion: In this pilot study, the extreme CYP2D6 genotypes (poor and ultrarapid metabolizers)
appeared to predict pain response and adverse events. Larger sample sizes will be needed to correlate
the whole range of genotypes with pain response.
52
4.3 Introduction
Pain is a major public health issue and it is the most common reason for physician consultation in
the United States (78). In Canada, more than 30% of the population is afflicted by chronic pain and
approximately 5% are taking codeine to manage pain at any given time (79). Despite a wide variety of
pharmacological agents available on the market, many people cannot achieve optimal analgesia;
inadequate treatment remains a major cause of suffering and dissatisfaction in pain therapy (80). One
cause for the variable success of pharmacologic pain therapy is different genetic polymorphisms
affecting patients’ pharmacogenomic response to analgesics.
Codeine, a commonly used opioid, acts on the mu-opiate receptor predominantly via its metabolite
morphine, which is formed almost exclusively by the genetically polymorphic enzyme cytochrome
P450 2D6 (CYP2D6). While in most people 10% of codeine is biotransformed into morphine,
multiple copies and multiple variations of the CYP2D6 gene affect the percentage of codeine
conversion into morphine and hence the analgesia and toxic responses to codeine(81). CYP2D6
genetic variants can be associated with increased, normal, reduced or null enzyme function resulting
in a wide range of phenotypic activity from excessive metabolism (Ultrarapid Metabolizers, UM) to
normal metabolism (Extensive Metabolizers, EM) to partial metabolism (Intermediate Metabolizers,
IM), to no metabolism of codeine (Poor Metabolizers, PM). There are currently more than 80 major
CYP2D6 allelic variants described (http://www.cypalleles.ki.se/cyp2d6.htm); to simplify genotype
interpretation, an activity score system which classifies individuals according to the number and
functionality of their CYP2D6 alleles can be used to predict their CYP2D6 enzyme activity (82),(83).
53
Postpartum pain, due to either c-section or episiotomy is a major source for the need for codeine,
with an estimated 30% of North American women using the drug (3). Kinetically, several studies
have examined the percent conversion of codeine into morphine for different metabolizers by
measuring morphine serum concentrations as the endpoint (84),(83),(80),(85),(86), (87),(88) . These
studies have identified that PMs convert very little codeine into morphine, whereas ultrarapid
metabolism can result in about 50% higher morphine plasma concentrations than normal. However,
there is much less information on the effect of CYP2D6 polymorphism on codeine
pharmacodynamics. Only four studies have examined the effect of CYP2D6 on codeine analgesia;
two using healthy volunteers (89),(90), and two in a clinical setting (91, 92). Given the dearth of
clinical studies, our objective was to study the relationship between CYP2D6 genotype and codeine
analgesia specifically among women post partum.
4.4 Materials and Methods
4.4.1 Patient s and Study Design
This was a nested cohort study within a recently published randomized controlled trial (RCT) (93)
(Clinical Trial Register: ISRCTN79265996) whereby 80 women who underwent elective c-section
provided an Ethylenediaminetetraacetic acid (EDTA) blood sample for CYP2D6 genotype analysis.
All pregnant women who were scheduled to have an elective c-section were approached during a
routine prenatal visit at the obstetrical clinic at St. Michael’s Hospital between September 1, 2008 and
March 31, 2009. Research protocol and informed consent were approved by the Research Ethics
Board at St. Michael’s Hospital.
All elective c-sections at St. Michael’s Hospital in Toronto were performed using the Pfannenstiel
protocol (46). Women who underwent elective c-sections received a spinal anesthesia with 0.75%
54
bupivicaine, and 15mcg fentanyl at induction, followed by 100 mcg of epidurally administered
morphine at the end of surgery. Women were routinely monitored in hospital for 3 days and then
discharged (i.e. approximately 75 hours after surgery).
Post c-section, the following analgesia protocol was administered, unless noted otherwise:
(1) A non-steroidal anti-inflammatory (NSAID): naproxen (500mg) rectally and then
orally every 12 hours for 48 hours.
(2) For break through pain: acetaminophen (300mg) with codeine (30mg) and caffeine
(15mg) (Tylenol no. 3, Johnson & Johnson, New Brunswick, New Jersey), 1-2 tablets
orally, every 4 hours pro re nata (prn).
(3) For mild to moderate pain: acetaminophen 500mg (Tylenol Extra Strength, Johnson &
Johnson, New Brunswick, New Jersey), 1-2 tablets orally, every 4 hours prn.
All medication consumption was recorded. To evaluate women’s rate of post operative recovery
we employed the Milestone Questionnaire, a scale previously used which comprises several items:
time to first hunger, first spontaneous voiding, first ambulation, first bowel movement, and first eating
solid foods after elective c-section (49).
4.4.2 Outcome Measures
The primary endpoint for the study was the Area Under The Curve (AUC) for pain in ambulation
for days 1-3 using the Visual Analogue Scale (VAS) (47, 48), corresponding to a person’s total pain.
VAS scores were collected (4x/day) ranging from zero (no pain) to ten (maximal pain) from all
women while they were in the hospital. The area under the VAS-time curve (AUC of pain) was
calculated by plotting the VAS scores over time and using the trapezoid rule. The formula is as
follows: 0.5(y0 + y1) ∆x, where y0 + y1 is the sum of the VAS scores and ∆x is the time elapsed
between the two measured VAS pain scores. This calculation was repeated until all available VAS
55
pain scores had been used in the calculation. The AUC was the sum of all the individual trapezoidal
calculations.
The following seven secondary outcome measures were collected or calculated: three day codeine
dose (total and mg/kg body weight), three day NSAID dose (total and mg/kg), number of adverse
events, peak pain (AUC of VAS scores on day 2), codeine dose day 2, genotype-adjusted morphine
dose and mean VAS pain scores. The following two co-variates were collected and used in the
multivariate analysis: mother’s age and neonate birth weight.
4.4.2.1 Genotyping CYP2D6
Blood samples for DNA extraction were collected from mothers during a routine blood draw in
triage on the labour ward and then stored at -80ᵒC. The blood sample from those women who took
Tylenol no.3 were genotyped for the presence of fifteen CYP2D6 alleles (*2, *3, *4, *5 (gene
deletion), *6, *7, *8, *9, *10, *12, *14, *17, *29, *41, *XN (gene duplication)) by using
AutoGenomics INFINITI® Analyzer and the CYP450 2D6I Assay (AutoGenomics Inc., Vista, CA,
USA). These 15 polymorphisms are the most frequently occurring alleles identified; included are the
most common alleles associated with poor (*3, *4, *5, *6), intermediate (*10, *17, *41), and
increased metabolism (gene duplications) in different ethnic populations (94). Alleles not carrying
any detected mutations were classified as *1 (wild type).
Assigning a CYP2D6 Activity Score
To predict the CYP2D6 metabolizer phenotype, we used the activity score system (81, 83)
whereby alleles with full CYP2D6 activity (*1, *2) are given a score of “1”, alleles with reduced
activity ( *9, *10, *17, *29, *41) a score of “0.5”, and inactive alleles (*3, *4, *5, *6, *7, *8, *12,
*14) a score of “0”. Genotype activity score which is obtained by summing up the scores of the
individual alleles in a given genotype was used to classify patients in four CYP2D6 phenotype classes
56
as follows: PMs had an activity score of 0; IMs an activity score ranging from 0.5-1.5; EMs an
activity score of 2; and patients carrying gene duplication in combination with two active alleles were
classified as UMs.
4.4.3 Statistical Analysis
The statistical analyses were performed on SPSS software, (IBM SPSS, version 17, Somers, NY).
Descriptive statistics were calculated for the independent variables and were checked for normality.
Multivariate and univariate (Spearman’s correlation) analyses were used to examine the relationship
between CYP2D6 genotype and analgesic response. Because our sample size was small and codeine
dose was non-normally distributed we used Spearman’s correlation to examine the relationship
between the dependent variable AUC of pain and the independent variable genotype-adjusted
morphine dose. The multivariate analysis using linear regression with stepwise method examined the
correlation between the independent variable AUC of pain and the dependent variable genotype group
(UM, EM, IM or PM) derived from genotype activity score, with the covariates of codeine dose
(mg/kg), NSAID dose (mg/kg), mother’s age and neonate birth weight. For missing data, we used the
last-observation-carried-forward method in the analysis of AUC and mean pain scores.
Model estimation of genotype-adjusted morphine dose
To evaluate whether genotype-adjusted morphine dose per kg can predict analgesia levels in a
univariate model, we used the CYP2D6 activity score to estimate morphine dose.
4.4.3.1 Estimating codeine metabolism rates
To estimate an individual’s morphine dose, we commenced with the assumption that EMs (those
with an activity score of 2) biotransform 10% of consumed codeine into morphine (83). To account
57
for genotype variability, a genotype-codeine conversion factor, as suggested by Kirchheiner et al (83),
was applied to the extensive metabolizer standard of 10% to account for increased or decreased
morphine production according to the CYP2D6 genotype. The factors were derived by taking the ratio
of plasma AUC of morphine over plasma AUC of codeine for each CYP2D6 (fine activity) genotype
group (83); ratios for the groups are as follows: UM (activity score of 3) =0.095; EM (activity score
of 2) = 0.064; IM (activity score of 1.5) =0.032; and PM (activity score of 0) =0.003. These ratios
were indexed to the EM group to develop a genotype-codeine conversion factor: 1.5 for UM, 1 for
EM, 0.50 for IM and 0.05 for PM.
4.5 Results
Of the 80 women in the original RCT, there were a total of 45 women who took Tylenol no.3 for
pain relief. Two women were not prescribed naproxen as first-line medication for analgesia and were
instead only prescribed acetaminophen with codeine. No women were taking CYP2D6 or CYP3A4
inhibiting medications during their hospital stay. The majority of women reported feeling pain most
acutely during the 2nd
day after the c-section. Patient characteristics for the 45 women are shown
(Table 6). Of these 45 women: 3 were UM (7%), 2 were PM (4%), 26 were IM (58%) and 14 were
EM (31%) (Table 7).
During days 1 and 2, a total of three pain intensity scores, which represented less than 1% of the
data, were not collected because the patients were sleeping during the time to record their level of
pain; all other data for patients were captured (pain medication consumption and time to first activity)
on these days. However on day 3, a total of 10 patients (22%) were discharged early (after 48 hours
instead of after 75 hours in hospital) resulting in 22% missing data (pain scores, pain medication
consumption and time to first activity). The main endpoint (AUC of pain) and all other secondary
58
measures were normally distributed, with the exception of codeine medication dose and adverse
events which were not normally distributed.
Three-day mean (±sd) pain AUC scores were 238 (±106) for the cohort; only the scores for the
UMs appeared higher 408 (±102). Three-day mean (±sd) pain scores for the cohort were 3.5 (±1.6);
three genotype groups reported similar scores, with the exception of UM which reported 6.0 (±1.5).
Three-day median codeine dose was 180 mg; this was the same for all genotype groups except the
PMs which was 450mg. Three-day genotype-adjusted morphine dose ranged from 0.007 – 1.1mg/kg
(Table 3).
59
Table 8: Patient Characteristics
Patient Characteristics All patients
Ultrarapid
Metabolizers
Extensive
Metabolizers
Intermediate
Metabolizers
Poor
Metabolizers
n=45 n=3 n=14 n=26 n=2
Ethnicity
caucasian 17 0 7 8 2
asian 14 0 2 12 0
hispanic 8 1 3 4 0
afro-american 5 2 2 1 0
arabic 1 0 0 1 0
Maternal age (years)
median 34 22.6 34.5 34 35.5
range 19-42 19-28 22-39 24-42 35-36
No. of previous c-sections
median 1 1 1 1 1.5
range 0-3 1-1 0-2 0-3 1-2
Weight of neonates (grms)
mean (± sd) 3463 (± 77) 3580 (± 557) 3548 (± 483) 3438 (± 550) 3027 (± 38)
range 2625-5315 3056-4165 2925-4400 2625-5315 3000-3054
Duration of c-section surgery (minutes)
mean (± sd) 41 (± 1) 41 (± 6) 41 (±12) 41 (± 11) 37 (± 6)
Gestational age of baby (weeks)
mean (± sd) 38.3 (± 0.1) 38.5 (±0.3) 38.6 (±0.1) 38.2 (±0.1) 37.8 (±0.4)
median 38.5 38.5 38.5 38 37.8
range 37 - 40.5 38-39 38-39 37-42.5 37.5-38
60
Table 9: CYP2D6 allele and genotype frequencies, activity scores and predicted phenotypes
CYP2D6 allele and genotype frequencies, activity scores and predicted phenotypes.
Allele Frequency Allele Frequency Allele Frequency
*1 30 (33%) *6 0 (0%) *12 0 (0%)
*2 18 (20%) *7 0 (0%) *14 0 (0%)
*3 0 (0%) *8 0 (0%) *17 3 (3%)
*4 14 (16%) *9 1 (1%) *29 1 (1%)
*5 2 (1%) *10 15 (17%) *41 6 (7%)
CYP2D6 genotype Frequency Activity score Predicted phenotype
*1/*2, *XN 1 >2 UM
*2/*2, *XN 1 >2 UM
*2/*17, *XN 1 ≥2 UM
*1/*2 7 2 EM
*1/*1 5 2 EM
*2/*2 2 2 EM
*1/*10 4 1.5 IM
*1/*41 3 1.5 IM
*2/*10 2 1.5 IM
*2/*17 1 1.5 IM
*1/*4 6 1 IM
*10/*10 3 1 IM
*17/*29 1 1 IM
*2/*4 1 1 IM
*4/*41 2 0.5 IM
*4/*10 1 0.5 IM
*4/*9 1 0.5 IM
*5/*41 1 0.5 IM
*4/*4 1 0 PM
*4/*5 1 0 PM
total 45
61
Table 10: Pain scores, medication dosing and milestone recovery times
Table 3: Pain scores, medication dosing, adverse events and milestone questionnaire results.
Results All patients
Ultrarapid
Metabolizers
Extensive
Metabolizers
Intermediate
Metabolizers
Poor
Metabolizers
n=45 n=3 n=14 n=26 n=2
Three-day post operative pain scores
AUC mean (± sd) 238 (±106) 408 (±102) 226 (±102) 226 (±100) 232 (±41)
mean (± sd) 3.5 (± 1.6) 6.0 (± 1.5) 3.3 (± 1.5) 3.4 (± 1.5) 3.4 (±1.0)
median 3.4 6.5 3.1 3.4 3.3
range 1.1 - 7.2 4.3-7.2 1.2-6.3 1.1-6.9 3.8-4.0
count of women >=4 mean VAS score 16 3 4 8 1
Day 2 (peak) post operative pain scores
AUC mean (± sd) 92 (±41) 159 (±31) 85 (±39) 89 (±39) 84 (±27)
mean (± sd) 3.6 (±1.7) 6.5 (±1.5) 3.3 (±1.5) 3.5 (±1.6) 2.9 (±0.9)
median 3.7 7.1 3.1 3.7 2.9
range 0.8-7.7 4.9-7.7 1.1-6.4 0.8-7.0 2.3-3.6
count of women >=4 mean VAS score 18 3 5 10 0
Three day codeine dose (mg)
median 180 180 180 180 450
range 30-840 60-540 60-840 30-660 120-780
Three day codeine dose (mg/kg)
median 2.4 3 2.2 2.4 4.6
range 0.4-11.1 0.7-6.8 0.8-10.8 0.4-11.1 1.6-7.7
Day 2 codeine dose (mg/kg)
median 0.8 0.7 0.9 1 1.5
range 0-4.6 0-3.8 0-4.6 0-3.7 0-3.0
Estimate three-day morphine dose (mg/kg)
median 0.22 0.4 0.2 0.1 0.02
range 0.007-1.1 0.1-0.9 0.08-1.1 0.02-0.8 0.007-0.04
Estimate day 2 morphine dose (mg/kg)
median 0.09 0.1 0.09 0.04 0.007
range 0-0.5 0-0.5 0-0.5 0-0.2 0-0.001
No. of adverse events from codeine
median 0 1 0 0 0.5
range 0-3 0-1 0-3 0-3 0-1
62
Table 3 continued
Time to first….
eating solid
foods flatus
bowel
movement ambulation
spontaneous
voiding
Total
Tylenol no.3
dose mg
(one dose =
60mg)
when Tylenol #3 was
consumed
mean (±sd) mean (±sd) mean (±sd) mean (±sd) mean (±sd)
Group of 80 24 (±10:45) 20 (±12:30) 58 (±16) 17 (±5:15) 17:30 (±5:15)
Cohort of 45 (those
taking codeine
medication) 25 (±12:30) 22 (±13) 60 (±13) 17:30 (±5) 17:30 (±5:15)
UM #1 (*2/*17, *XN) 14:05 13:05 75:00+ 25:35 21:15 540 throughout 3 days
UM #2 (*1/*2, *XN) 18:55 12:25 57:25 23:25 23:25 60 dose on 1st day
UM #3 (*2/*2, *XN) 23:45 3:45 75:00+ 20:45 20:45 180 throughout 3 days
PM #4 (*4/*4) 28:45 20:45 48:45 10:45 15:45 120 both doses on 1st day
PM #5 (*4/*5) 15:43 13:13 75:00+ 13:13 13:13 780 throughout 3 days
Notes: 75:00+ denotes that this had not yet occurred at time of hospital discharge;
Time reported in hours and minutes; minutes have been rounded to the nearest 5 minute intervals
63
4.5.1 Relationship of genotype to pain outcomes
Due to the relatively small numbers of extreme genotypes, this pilot study was underpowered to
show overall relationship between genotype and pain response. Spearman’s correlation indicated no
overall correlation (n=45, rs= 0.034, p=0.44) was found between AUC for pain and genotype-adjusted
morphine dose for the group.
The multivariate model approached significance (F=7.615, r2 = 0.15) for the covariate mother’s
age (beta= -7.736, p=0.068) explaining AUC of pain. All other variables were non-significant: total
codeine dose/kg (p=0.998), total NSAID dose/kg (p=0.925), neonate birth weight (p=0.987), EM
genotype group (p=0.998), IM genotype group (p=0.969) and PM genotype group (p=0.990).
Multiple linear regression for peak pain (day 2) was significant (F=4.600, r2=0.097) for mother’s
age (beta = -2.377, p=0.038) while all other variables were non-significant: EM genotype group
(p=0.998), IM genotype group (p=0.969), PM genotype group (p=0.990), neonate birth weight
(p=0.945), day2 NSAID dose mg/kg (p=0.956) ,and day2 codeine dose mg/kg(p=0.888).
4.5.2 Individual analysis of extreme genotypes
Because the vast majority of patients were, as expected, EM and IM, we examined the pain and
analgesia effects of our extreme cases (UMs and PMs). Pictorial representation of individual pain
scores and Tylenol no.3 consumption are shown (Figure 1).
Ultrarapid Metabolizers
Each of the three UMs had one of the previous factors identified by us recently (93) to be
associated with increased perceived pain after c-section; two were young (19 and 21 years old) and the
third gave birth to a baby over 4000 grams. Despite the higher level of pain for these three women, 2
64
of the women requested only small doses of Tylenol no.3 (60 mg once and 60mg thrice respectively)
preferring instead to take Tylenol Extra Strength and naproxen or naproxen alone for pain relief due to
dizziness and constipation. The third UM was not prescribed naproxen for 48 hours post surgery as
per protocol but instead was only prescribed Tylenol no.3 prn to relieve pain. She took 540mg
Tylenol no.3, (60mg, nine times) throughout her three day hospital stay and while she did not note any
side effects, she had not yet had a bowel movement at the time that she was discharged from the
hospital (75 hours post surgery) (Table 3).
Poor metabolizers
The two PMs were both >35 years old, a factor associated with less pain response after c-section.
Despite lower pain levels, neither of these women reported any reduction in pain after consuming
Tylenol no.3. One PM woman took 120mg of Tylenol no.3 (60mg, twice) and then switched to
Tylenol Extra Strength because she did not feel that the Tylenol no.3 was relieving her pain. The other
PM women took 780mg (60mg, 13 times) over her three day period; while she also did not report any
pain relief from Tylenol no.3, she had not yet had a bowel movement at the time of hospital discharge
(75 hours post surgery).
65
Figure 4: Individual analyses
Individual pain scores and analgesic medication timeline for UMs and PMs of codeine. Solid arrows
represent ingestion of Tylenol no.3 (60mg) and broken arrows represent ingestion of Tylenol Extra
Strength (1000mg). In addition to the medication shown on graphs, all patients received NSAIDS for
48 hours post surgery, except patient #5.
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4.6 Discussion
This study compared clinical pain relief among women of varying CYP2D6 genotypes who took
codeine-containing medication after an elective c-section.
In our recently published randomized trial (93)we identified 2 factors associated with women’s
perception of pain after c-section; mother’s age (negative correlation) and neonatal birth weight
(positive correlation). When AUC of pain was regressed against total codeine consumption, total
NSAID consumption, CYP2D6 genotype group, mother’s age and neonatal birth weight, the only
significant factor was the mother’s age. Older patients’ experience of pain may differ from that of
younger patients due to both physiological and psychological reasons as has been suggested before
(95), (96) . Additionally, older patients have been reported to enjoy more pain relief than younger
patients from the same dosage of medication (97).
Our univariate and multivariate models examining CYP2D6 genotype and codeine dose showed
no correlation to AUC of pain. We used pain AUC scores as a measure of total pain as this metric is
simple to calculate, easy to explain and captures two dimensions of the pain (magnitude and duration)
in a single continuous measure (98).
The lack of overall correlation between AUC of pain and genotype-adjusted morphine dose in the
univariate and AUC of pain and codeine dose in the multivariate models is expected due to the fact
that most patients were EMs and IMs, with relatively small numbers of extreme cases in which
CYP2D6 genotype has shown large effects.
The potential effects of CYP2D6 genotype could be illustrated in the individual cases of UMs and
PMs providing valuable insight into patients where CYP2D6 polymorphism polymorphism is
clinically relevant. While one PM and two UMs had low doses of codeine-containing medication (i.e.
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120 mg, 60mg and180mg respectively over 3 days) to control breakthrough pain, the reasons for these
low doses were markedly different. Both UMs stopped taking the drug because of side effects, while
the PM did not feel that the codeine-containing medication was helping her pain. In contrast, while
the other PM also noted that the medication was not providing analgesia, she instead repeatedly
requested codeine-containing medication, until she was receiving the maximum daily dose (60mg
every 4 hours for 3 days). The one UM with high doses of codeine-containing medication was
unfortunately not prescribed naproxen as per the standard analgesia protocol, and as such was left with
little option for pain relief. The two UMs and one PM that took codeine-containing medication
throughout their three day hospital stay had not yet had a bowel movement at time of hospital
discharge; this length of time is outside the mean (±sd) time for the cohort (60 ±13 hours). This is
consistent with previous literature showing that adverse effects arise from codeine ingestion, not just
morphine, and occur regardless of CYP2D6 genotype status (89).
The strengths of this study include being one of the first studies to examine CYP2D6 genotype and
codeine analgesia in a clinical setting, and the first to do so post partum. Since one researcher
collected almost all of the pain score and secondary data, she was able to collect qualitative
information about the patient’s pain and why patients switched from one medication to another.
Potential limitations of this study include the small, underpowered sample size which precluded
meaningful numbers of patients in different genotype groups to show correlation Moreover, the
interpretation of genotypes and the resulting estimate of codeine and metabolites may be over or
underestimated. While we were able to secure a blood sample for genotyping during a routine blood
draw prior to surgery, the vast majority of women were unwilling to provide additional blood samples
for pharmacokinetics of codeine-containing medications for post-partum pain. A large inter-
individual variability in response to codeine has been reported in an experimental study among
extensive metabolizers (99) and those with reduced function alleles (100) and this has not been
68
captured in this paper. In addition, the *1 allelic variant was assigned as a default if none of the other
14 alleles were present and hence some rarer alleles could have been missed.
In addition, there are genetic factors which may modify the effect of morphine, including
variability in the expression or signaling of the mu-opioid receptor (101) (102) , variability in the
MDR1 gene which codes for the P-glycoprotein used for drug transport (103), variability in other
codeine metabolizing enzymes such as CYP3A(104), and UGT2B7 (105). There are also non-genetic
effects such as variations in CYP3A activity due to pregnancy (106) and surgery (107), and non-
genetic factors such as age, race, mood, and coping ability (108). Moreover, large variability in the
process of nociception (109) would lead to great inter-patient variability in recorded pain scores and
the desire for pain medication. The inability of the pain scores to differentiate patients may be due, in
part, to issues other than pain severity. Concerns about adverse effects, medication interactions, and
addiction, may all contribute to the decision to accept or reject treatment (110).
Finally, our analgesic protocol follows the WHO analgesic ladder for progressive treatment of
increasing pain (111) . All women, except two, were given NSAIDs for 48 hours post surgery, but
this cannot lead to the assumption that the effect of the NSAID was similar across all women.
4.7 Conclusions
In this pilot study, extreme CYP2D6 genotypes appeared to predict pain response or adverse
effects. To study the whole range of genotype-phenotype correlation, these observations should be
confirmed with a much larger cohort study, with larger proportions of ultrarapid and poor
metabolizers.
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Chapter 5
70
5 General Discussion
5.1 Summary
Pain is a complex phenomenon to which an individual's response is determined by the interactions
of physical, psychological, and cultural factors (112) . Despite a variety of pharmaceutical agents
available, acute and chronic pain are often not well controlled. The goal of this thesis was to examine
the effect of distant Reiki on postpartum pain as well as to study the relationship between CYP2D6
genotype and codeine analgesia.
Because Reiki, being a CAM therapy, is not a typical subject which is studied in the
Pharmaceutical Sciences department I have included my knowledge transfer (KT) plan as well as my
suggestions for healthcare policy in a hospital setting.
Einstein once said if he had only 1 hour to save the world, he would spend 55 minutes defining the
problem and only 5 minutes finding the solution. We followed a similar intellectual process in
designing this study. Most CAM studies are considered “poor quality” in that they do not follow the
CONSORT criteria for randomized trials and are at risk for introducing bias; Reiki studies were no
exception. While the majority of Reiki studies yielded positive responses, our quality analysis
indicated that all existing studies lacked in one of the three key areas of proper patient allocation
concealment, randomization or blinding. As improper design or execution in any of these three areas
can jeopardize internal validity and lead to the introduction of bias, we paid careful attention to the
design of our study. The following four examples provide insight into the intellectual process of
ensuring a high quality randomized controlled trial. Firstly, because of a personal incident, I had
71
wanted to try using Reiki to relieve pain in children; however, measuring children’s pain is too
complex and inconsistent. Instead, we chose women who were to undergo elective c-sections. By
asking women to rate their own pain, we avoided requiring a researcher to evaluate a child’s pain level
and the bias that can be introduced with inter-evaluator differences.
Secondly, by using a single hospital which used a standardized procedure for c-section, and had a
standardized pre and post c-section analgesia protocol, we could ensure that the pain we were
inducing and measuring was a “standardized inflicted pain” and that the difference in analgesic
medication consumption between groups could be measured.
Thirdly, by enrolling patients at St. Michael’s Hospital and having them confidentially assigned to
a study arm by a Hospital for Sick Kids coordinator who had never met them, we ensured that patient
enrollment into each of the two study arms was concealed from all St. Michael’s Hospital research
and hospital staff as well as the patients themselves.
Fourthly, by using distant Reiki instead of traditional hands-on Reiki, we ensured blinding of all
participants, researchers and medical staff involved in the trial. This was a key component in the
design of the study as it allowed us to rule out the placebo effect.
To ensure that we captured any potential effect from the distant Reiki, we collected pain scores,
cumulative dose equivalents of pain medication required, and milestones of rate of recovery. In this
way, if pain rates were the same between Reiki and non-Reiki groups, but pain medication
requirements were less in the Reiki group, we could attribute the difference to the effect of Reiki.
Likewise, as Reiki energy is believed to go “wherever the patient needs it”, we captured recovery time
from c-section (ie. time to first bowel movement, ambulation, etc) to compare if Reiki patients healed
faster than non-Reiki patients. The results of the study were negative, indicating that distant Reiki is
72
not effective for post c-section pain. However, the mean pain scores over three days for both the
Reiki and the control groups were less than or equal to 4 on the VAS pain scale (Figure 2) indicating
both groups felt a “low” level of pain (48); the low VAS pain intensity scores for both groups could
be a potential reason for not finding a significant difference between the two groups.
Sixteen of the women (20%) in the Reiki study were discharged on the morning of day 3, instead
of the morning of day 4, leaving a 24 hour gap in our dataset. To accommodate for the missing data I
used the last-pain-score-carried-forward method in my analyses. To ensure that our method of last-
pain-score-carried-forward did not adversely affect our results, I conducted several sensitivity tests on
the data. First, I assessed whether the number of patients who were discharged early differed by
group, to determine whether one group would have more imputed data than the other. Fortunately,
both groups had the same number of patients who were discharged early – eight (8). Second, I
evaluated the AUC of VAS pain scores on day 1 and day 2 individually (both days had full data sets)
and compared those analysis to my primary endpoint of AUC of VAS pain scores for days1-3
combined and found a similar trend. Though the last-pain-score-carried-forward method probably
overestimated the intensity of women’s pain on the 3rd
day (since these women were feeling well
enough that they wanted to go home), based on my sensitivity analyses, I believe that it was a sound
approach to approximating the missing data..
From a knowledge translation perspective, our goal (which we achieved) was to publish this study
in a medical journal rather than a CAM journal, so we could reach a diverse audience (conventional
practitioners as well as CAM practitioners). Regardless of the study’s outcome, publishing a well
designed, rigourous CAM trial sends the message to the medical researcher community that all
treatment modalities need to be researched in a quality manner. I bring this up, because I often
received negative attention from my own faculty because of my research topic; many researchers had
73
already concluded that Reiki was bogus and as such, did not warrant a proper study. As researchers,
we need to create a climate whereby all subjects can be rigorously studied, instead of being dismissed
prior to study. Without well designed and executed studies, policy and treatment options become a
function of beliefs rather than evidence-based. This is particularly important in the area of pain where
inadequate pain treatment remains a major source of suffering and dissatisfaction in pain therapy,
despite the plethora of pharmaceutical agents (113).
One of the reasons I chose to study Reiki was because of its widespread and growing use by both
lay people and alternative care providers. Despite millions of dollars being spent on this
complementary therapy, very little literature existed on its effectiveness, and the literature that did
exist all claimed positive results. However, as already mentioned these studies were not properly
randomized or blinded, and the patients and researchers knew which patients were in the Reiki group
as a Reiki practitioner was present to provide the therapy. The resulting positive result from Reiki in
the previous pain studies could be due to the placebo effect which is a real physiological effect
whereby the body releases endogenous opioids which bind to the mu-opioid receptor (REF).
Although the results of this trial were not positive, there are important implications for healthcare
professionals and lay people in terms of healthcare policy using distant Reiki. While 40% of patients
use CAM therapies for healthcare, a major patient complaint is the lack of evidence supporting CAM
treatments (24), yet despite the lack of evidence, individuals still purchase CAM therapies as an out
of pocket expense. Some hospitals are evaluating whether or not to provide Reiki treatments for pain.
While the evidence for distant Reiki does not support a hospital policy of offering (and paying for)
Reiki services, a policy could exist which would allow individuals to pay for and bring in their own
Reiki therapist. As long as the safety and liability requirements of the hospital are addressed; this type
74
of policy allows individuals to tailor their own approach for wellbeing, and allows those individuals
who do benefit from Reiki to continue to do so, whether due to placebo effect or otherwise.
We were able to find a relationship between codeine analgesic effect and extreme CYP2D6
genotypes, the clinical information from the individual examination of the ultrarapid and poor
metabolizers provided valuable insight into the codeine – genotype relationship. The women who
were ultrarapid and poor metabolizers provided clues to their genetic disposition through their
response to codeine dosing (either through adverse effects or not feeling an analgesic effect). Patient
clues need to be recognized by healthcare providers and used to inform pharmacotherapy choice.
5.2 Strengths and weaknesses
Several strengths exist in the research presented here. These include the rigorous study design,
data collection and analysis which supports a high degree of internal validity. Internal validity is a
necessary, but not sufficient, condition for a study to provide a useful clinical observation. The other
condition, external validity, is the degree to which the results of an observation hold true in other
settings. Given the broad socio-demographic patient base which is serviced by St. Michael’s Hospital,
our study had patients originating from all continents giving our study a high degree of external
validity (or generalizability).
Limitations of the research presented here include the small sample size for the pharmacogenetic
analysis of codeine, as most patients had the more common Extensive or Intermediate metabolizer
status.
75
5.3 Conclusions
Alleviating pain after c-section is important as studies have shown that post operative pain
negatively affects a mother’s ability to care for and breastfeed her infant. While opioid toxicity from
codeine can cause adverse effects in ultrarapid metabolizers or lead to untreated pain in poor
metabolizers, certainly not all women need to avoid the use of codeine. For those women who chose
to have codeine-containing medication, special note should be made of side effects or lack of pain
reduction, and alternatives to opioids should be sought out. For those wishing to avoid opioids for
pain relief, distant Reiki is not recommended as a method to reduce pain after c-section.
5.4 Implications for future work
The non-significant findings of distant Reiki on all measures of analgesia and recovery after
surgery led to the unequivocal finding that distant Reiki is not suitable to reduce pain after c-section.
These findings are limited to our study population of women who underwent elective c-section and
received a daily dose of distant Reiki over three days. Researchers may want to investigate distant
Reiki for other types of pain, and with different dosing regimen.
For researchers who wish to evaluate whether or not an effect of distant Reiki is purely due to the
placebo effect, our model would require four arms: These four arms would contain patients who
received the following information and treatments :(1) those told they would receive distant reiki and
do receive it, (2) those told they would receive distant reiki but do not receive it, (3) those not told
they would receive distant reiki but do receive it, and (4) those not told they would receive distant
reiki and do not receive it. By comparing the results of those who think they are receiving distant
Reiki (but are not) with those who think they are receiving it (and actually do receive it) we would be
able to discern the magnitude of the placebo response. By comparing the results of the group that
76
thinks they are receiving distant Reiki (but does not) to the group that does not know they are
receiving distant Reiki, we would be able to discern whether or not there is a true impact from the
treatment. Because the pain scores in my distant Reiki trial were considered “low” (ie. mean scores of
4 or less for both Reiki and control groups), future researchers may wish to power their study with a
lesser than 25% reduction in pain (i.e. 10% reduction) to see if the effect is detectable.
To study the relationship between CYP2D6 genotype and codeine analgesia, researchers may want
to recruit patients from the genetic extremes, using larger populations of known ultrarapid and poor
metabolizers of codeine.
77
Chapter 6
78
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CHAPTER 7
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7 List of Publications
1. vanderVaart, S., Gijsen, V.M.G.J., de Wildt, S.N., Koren, G. A systematic review of the
therapeutic effects of reiki. J Altern Complement Med 2009; 15; 1157-69
2. vanderVaart S, Hogan ME, Einarson TR. Assessment of the bioequivalence. Clin Ther. 2010
Feb 2010;32(2):398, author rey 399; susson 399.
3. vanderVaart S, Berger H, Tam C, Goh YI, Gijsen VMGJ, de Wildt SN, et al. The effect of
distant reiki on pain in women after elective caesarean section - a double blinded randomized
controlled trial. BMJ Open 2011; DOI: 10.1136/bmjopen-2010-000021.
4. Hogan M,E. vanderVaart, S., Perampaladas, K,, Machado, M. Einarson, T.R., Taddio, A.
Systematic review and meta-analysis of the effect of warming local anesthetics on injection
pain Ann Emerg Med 2011; DOI: 10.1016/j.annemergmed.2010.12.001.
5. vanderVaart, S., Berger, H., Sistonen, J., Madadi, P., Matok, I., Gijsen, V.M.G.J., de Wildt,
S.N., Taddio, A., Ross, C.J.D., Carleton, B.C., Hayden, M. R., & Koren.G.CYP2D6
polymorphisms and codeine analgesia in post partum pain management: a pilot study.
Therapeutic Drug Monitor 2011 (accepted for publication)
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CHAPTER 8
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8 Appendices
Appendix 1: Data collection forms
Date:_____
It is important that the patient fill out this form herself or tell someone the score.
Please complete one form each day during your hospital stay.
1. Pain Scale in rest: Please score your pain in rest on this scale.
0 = no pain, 10 = worst pain
0 10 No Pain Worst Pain
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2. Pain Scale with movement:
Please score your pain on this scale when you move or walk.
0 = no pain, 10 = worst pain.
0 10
No Pain Worst Pain
3. Pain at night
What was your level of pain at night pain (from 0-10)?______________
0 10
No Pain Worst Pain
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4. The Activity Milestone Questionnaire
Please fill out this questionnaire a precisely as possible. Write down the time in hours, please.
Activity Date Time
First vomiting:
First hunger:
First eating solid food:
First flatus:
First bowel movement:
First walking:
First urine:
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5 Patient Intake Information
Ethnicity Caucasian Arabic
Afro-Caribbean Asian
Hispanic Other
Age: years
Weight: kg/lb
Previous C-section: Yes No Number:
Previous vaginal delivery: Yes No Number:
Previous surgery: Yes No
Previous injuries/
Chronic pain
(Duration of pain,
Medication, how long?)
In your opinion, how well do you manage pain on a scale of 1-10 with 1 being very poor, and 10 being very
well? ______________________
Parity/Gravida history:
P________ G__________ T________ A________ L________
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Appendix 2: St. Michael’s Hospital documentation
Consent to participate in a research study
Study Title: The effect of Reiki on pain in women who will undergo non-emergency caesarean section and the
effect of genetic variations on the use of codeine
Study Investigators:
St. Michael's Hospital Principal Investigator
(study doctor): Dr. Howard Berger (may also be the treating
doctor)
Perinatologist, Head of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology,
St. Michael’s Hospital,
Phone: (416) 867-7460 Ext 8408
Overall Principal Investigator (study doctor):
Dr. Gideon Koren, Professor of Pediatrics, Pharmacology, Pharmacy,
Medicine and Medical Genetics, The University
of Toronto, Senior Scientist, The Research Institute,
The Hospital for Sick Children, Clinician-
Scientist,
Phone: (416) 813-1500 Ext. 5781 Co-investigators:
Dr. Saskia de Wildt, Pediatrician, The Hospital for Sick Children
Dr. Anna Taddio, The Hospital for Sick Children Sondra Vander Vaart, PhD student, University of Toronto, Department of Pharmacology
Violette Gijsen, Medical student, The Hospital for Sick Children
Time of availability of investigators: Monday – Friday 9:00 am – 5:00 pm
Introduction
Before agreeing to take part in this research study, it is important that you read the information in this research
consent form. It includes details we think you need to know in order to decide if you wish to take part in the
study. If you have any questions, ask a study doctor or study staff. You should not sign this form until you are
sure you understand the information. All research is voluntary. You may also wish to discuss the study with
your
family doctor, a family member or a close friend. If you decide to take part in the study, it is important that you
are completely truthful about your health history and any medication you are taking. This will help prevent
unnecessary harm to you.
Conflict of Interest
There is no perceived or actual conflict of interest among the members of the research team.
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Study Sponsors
This is an investigator initiated study. This research is funded by internal resources from the hospital; no
commercial (drug) companies are involved.
Purpose of the Research
Codeine is commonly used after delivery for pain following a caesarian section. As most mothers breastfeed
their newborns, the safety of codeine and its active metabolite, morphine, in breastfed infants is of primary
concern. Codeine has been taken by millions of mothers who breastfeed. However, it would be best if we could
find ways other than using drugs to reduce pain after caesarian section. Many people who are in pain use
complementary and alternative medicine. One method to reduce pain may be Reiki therapy. Reiki is an ancient
Japanese form of healing. Reiki works by the transfer of positive energy from the healer to the patient. This can
be done by directly touching the patient or by thinking about the patient from a distance. Other researchers have
studied the effect of Reiki. It seems to help for different problems, such as pain. However, nobody has studied
if Reiki can reduce pain after caesarian section.
The first aim of this research is to study the effect of remote Reiki on pain in women after caesarian
section.
We also know that some women and their breastfed babies respond differently to pain medication than others.
In the last year, it has become clear that variation in genes may explain part of this.
The second aim of this research is to study how both your genes and your baby’s genes may influence
how both of you respond to pain.
We are asking you to consider participating in this study to help us determine whether remote Reiki reduces the
amount of pain and increases the rate of healing in women who have non-emergency cesarean sections, and to
better understand genetically determined responses to codeine.
Description of the Research
If you agree to participate in this study, you will be randomly placed (like tossing a coin) into one of two
groups, based on a computer generated random assignment, by an independent researcher at The Hospital for
Sick Children. One group will receive remote Reiki and the other will not. Both groups will have access to
standard pain control medication as needed. If you agree to participate in this study, after your caesarean
section you will be asked to fill out a pain score four times per day as well as a questionnaire once a day. We
will also take a few drops of your blood (1 mL or 1/5 teaspoons) during routine blood work to look at genetic
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variation in how you respond to pain and pain medication. Routine blood work sometimes causes minor
discomfort or bruising.
In the event that you are randomly assigned to receive remote Reiki, the independent researcher will contact the
Reiki practioner. You have a 50% chance of being placed into either group. Neither you nor the researcher
who records your information will know if you are in the Reiki group or not. This will prevent the researcher
from providing any leading information to you or from “observing” outcomes that they would like to see (this
is called Observer Bias).
This type of study is referred to as a double blind study. The double blind method is an important technique to
gather observable and measurable evidence, and prevents research outcomes from being 'influenced' by either
the placebo effect or by observer bias.
One group will receive three sessions of remote Reiki (on days 1, 2 and 3 for 20 min each day) in addition to
having access to the standard pain control medication. Women in the remote Reiki group will not know what
time of day the Reiki session will be taking place. The other group will receive only the standard pain control
medication and no Reiki.
We are doing this study at the Department of Obstetrics & Gynecology at St. Michael’s Hospital. We will study
80 women (and their babies) who will undergo non-emergency cesarean sections. We will collect your data
(information) for a maximum of 72 hrs after the caesarian section.
As part of the study, the following information will be collected:
1. You will be asked to fill out the Visual Analogue Scale (VAS) for pain four times/day (7-9:30am, 12-2:30pm, 5:30-8:00pm, during the morning for the night before) over a period of three days, which will
take approximately 30 minutes in total during these 72 hours. The VAS is a score that rates your level
of pain from No Pain (0) to The Worst Possible Pain (10) at a given period of time. 2. In addition, you will be asked to fill out a Milestone questionnaire, once a day for three days. This
questionnaire will ask you about your recovery after surgery. This questionnaire will take
approximately 30 minutes in total to complete during the 72 hours. You may skip questions that you
do not wish to answer. 3. A researcher will record your total opioid dose (for example, codeine or morphine) and other relevant
clinical information and medications from your hospital chart. If you want to see the exact list of
clinical information that we would collect from you, you can ask us to give it to you. 4. A researcher will determine from your blood and your baby’s blood sample what your genetic make-up
is, based on how you respond to pain and to drugs that control pain.
5. A researcher will record your baby’s respiratory rate from the hospital charts. This can be used to
determine how comfortable your baby is and/or if your baby has side effects from the pain medication
you are taking.
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Genetic Testing
DNA is the genetic material of all cells. Segments of DNA are called genes. Scientists are conducting research
to learn about how our genes (DNA inherited from our mother and father) affect our physical features and
health. We know some genes control the colour of a person's hair or eyes, others affect individual responses to
particular medicines, and yet others cause or increase one's risk of certain diseases.
A few drops (1mL or 1/5 teaspoons) of your blood and your baby’s blood will be taken during a routine blood
sample to determine your genetic make-up for your response to pain and to drugs that control pain. These tests
will include looking at the genes with the names CYP2D6, OPRM1, COMT, UGT. This field of research is
changing very rapidly. New genes that determine how you respond to pain may be discovered in the near
future. If this happens, we will also look at these genes. We will not look at other genes.
About Your Blood Sample and your Baby’s Blood Sample
Your blood sample and your baby’s blood sample (and the genetic material obtained from your blood) will be
stored under the direction of Dr. Gideon Koren in a secure storage space in a limited access facility at the
Hospital for Sick Children until such time as the sample is completely used up, for 7 years, or until the research
is complete (whichever is later). This sample will be sent from the study laboratory located in the Hospital for
Sick Children to the Pharmacogenomics Core Laboratory, Clinical Chemistry Department, Erasmus MC
Rotterdam, the Netherlands for final analysis. No personal identifiable information will be sent to this
laboratory. The participant study-ID key will remain with Dr Howard Berger in paper form in his office in a
locked cabinet at St Michael’s Hospital. A digital file with the identifiable information will be stored on the
password-protected St. Michael’s Hospital network. Only Dr. Howard Berger and the researcher will have
access to this file.
These blood samples will only be used for the purposes of this study. Only the study researchers and staff will
have access to the samples. The results of your genetic testing will be included in a study database with your
VAS scores, your opioid use and your answers to the questionnaire. The results will be analyzed collectively
(all together); no individual data will be reported. The results of the genetic testing will not become part of your
personal medical record. As we do not know yet how your genetic make-up may help you when you are in
pain, we can not give you the results of this test. If you wish to withdraw your blood sample, you can contact
Dr. Howard Berger who holds the identifying key.
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Potential Harms (Injury, Discomforts or Inconvenience)
We know of no harm or inconvenience that taking part in this study could cause you. There are no reports in the
literature that remote Reiki can cause harm. You may have mild inconvenience from this study, as we will ask
you at least four (4) times daily, for three days, to tell us how much pain you have and how well you are
recovering (VAS scores and questions about your recovery).
Potential side effects of opioids (such as codeine) include: nausea, constipation and abdominal pain, amongst
others. You would experience these side effects regardless of whether you participated in this study or not, if
you took any opioids.
Blood from you will be drawn together with blood work that is ordered by your doctor. This may slightly
prolong the time for blood sampling. Blood from your baby will not be taken directly from your baby, but from
the umbilical cord immediately after birth. We do not know of any risk/harm this can cause.
The greatest risk in this study is the unintentional release of information from your health records. The study
doctors will protect your records and keep private all the information in your study file, including your name,
address and telephone number. The chance that this information will be accidentally given to someone else is
extremely small.
If the genetic information from your blood or your baby’s blood samples were released to you, your family, or
other persons such as employers or insurers (referred to as “third parties”), it is possible that it could be used to
prevent you from obtaining employment or insurance. In order to minimize any such risks, and since the results
of these studies are not expected to benefit you directly or to alter your course of treatment, the researchers
have taken special precautions to keep your genetic information confidential so that it cannot be obtained by
third parties. This means that the blood sample you provide will be coded with a study number (not your name)
to ensure that persons outside of the study will not be able to identify you.
Reproductive Risks
There are no known reproductive risks related to participating in this study.
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Potential Benefits
To individual subjects:
You may or may not benefit from participating in this study. If you participate in this study and are not in the
Reiki group, there are no known benefits.
To society:
This study is one of many that examine the effects of complementary medicine in a western hospital setting.
By participating in this study, you will aid medical researchers in collecting scientific evidence of non-
pharmaceutical pain control techniques. Since we know that opioids may have unwanted side effects, other
mothers who are scheduled to receive opioids in the future may benefit from this research.
Protecting Your Health Information
The study researchers, coordinators, and delegates (hereby referred to as “study personnel”) are committed to
respecting your privacy. No other persons will have access to your personal health information or identifying
information without your consent, unless required by law. Any medical records, documentation, genetic
information, blood samples, or information related to you will be coded by study numbers to ensure that
persons outside of the study will not be able to identify you. No identifying information about you will be
allowed off the hospital premises. All information that identifies you will be kept confidential and stored and
locked in a secure place that only the study personnel will have access to. In addition, electronic files will be
stored on a secure hospital or institutional network and will be password protected. It is important to
understand that despite these protections being in place, experience in similar studies indicates that there is the
risk of unintentional release of information. The principal investigator will protect your records and keep all
the information in your study file confidential to the greatest extent possible. The chance that this information
will accidentally be given to someone else is small.
Results of the genetic testing are for research purposes only, and will not be made available to you, members of
your family, your treating doctor, or other third parties, except as required by law. The results of the genetic
testing will not become part of your personal medical record.
By signing this form, you are authorizing access to your medical records by the study personnel and the St.
Michael’s Hospital Research Ethics Board. Such access will be used only for purposes of verifying the
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authenticity of the information collected for the study, without violating your confidentiality, to the extent
permitted by applicable laws and regulations.
National and Provincial Data Protection regulations, including the Personal Information Protection and
Electronic Documents Act (of Canada) or PIPEDA and the Personal Health Information Protection Act
(PHIPA) of Ontario, protect your personal information. They also give you the right to control the use of your
personal information, including personal health information, and require your written permission for your personal information (including personal health information) to be collected, used or disclosed for the purposes
of this study, as described in this consent form. You have the right to review and copy your personal
information. However, if you decide to be in this study or chose to withdraw from it, your right to look at or
copy your personal information related to this study will be delayed until after the research is completed.
Communication with the Primary Care or Treating Doctor
The study team will not request information about you from your primary care doctor. The study team
recommends, however, that your primary care doctor be informed of your participation in this study.
Please initial here______ to indicate your consent for the study team to notify your primary care doctor of your
involvement in this study.
Potential Costs of Participation and Reimbursement to Participants
There are no costs involved with your participation in this study. You will receive no reimbursements or
incentives for participating in this study.
Compensation for Injury
If you suffer an injury from participating in this study, medical care will be provided to you in the same manner
as you would ordinarily obtain any other medical treatment. In no way does signing this form waive your legal
rights nor release the study doctor(s), sponsors or involved institutions from their legal and professional
responsibilities.
Participation and Withdrawal
Participation in any research study is voluntary. You do not have to participate in this study if you do not want
to. If you choose not to participate, you and your family will continue to have access to customary care at St.
Michael’s Hospital. If you decide to participate in this study you can change your mind at any time without
giving a reason, and you may withdraw from the study at any time without any effect on the care you and your
family will receive at St. Michael’s Hospital. If you choose to withdraw from this study, please contact a
103
member of the study team. You may also withdraw your blood sample or your baby’s blood sample at any
time by making a request to the study doctor or study nurse. Although your sample will be withdrawn upon
your request, any data already obtained from your sample cannot be withdrawn or destroyed.
If you withdraw from the study, we will keep your results and mark them as “incomplete” (similar to a
participant who is withdrawn from the study for other reasons; e.g. re-surgery in 72 hrs). We will not use the
incomplete data for formal analysis, but we do need to know if there is a trend for participants who withdraw
from the study (i.e. for example, all have higher pain scores).
New Findings or Information
New information from this study or other studies may affect whether you want to continue to take part in the
study. If this happens, we will tell you about this new information. In some situations, the study doctor may
decide to stop the study. If this happens, the study doctor will talk to you about what will happen next.
Research Ethics Board Contact
If you have any questions regarding your rights as a research participant, you may contact Dr. Julie Spence,
Chair, Research Ethics Board at St. Michael's Hospital at (416) 864-6060 x2557 during regular business hours.
Study Contacts
If you have any further questions about this research study you may contact Dr. Howard Berger at (416) 867-
7460 Ext 8408 or Dr. Gideon Koren at (416) 813-1500 Ext. 5781
Study Results and Publication
Once the results from the 80 women and their babies have been collected, we plan to publish a report (and
perhaps do presentations) which documents the effect of Reiki on pain and healing in women with non-
emergency caesarean sections. Individual data will not be reported; data will only be reported in aggregate
(group) form (i.e. results of Reiki group vs. non-Reiki group).
You can ask us to send you a copy of the report when it is published by contacting Dr. Howard Berger, the
principal investigator.
If you wish to receive the results from this research study, please initial here _______.
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CONSENT FORM
Study Title: The effect of Reiki on pain in women who will undergo non-emergency caesarean section and
the effect of genetic variations on the use of codeine
The research study has been explained to me and my questions have been answered to my satisfaction. I have
been informed of the alternatives to participation in this study. I have the right not to participate and the right
to withdraw without affecting the quality of my medial care at St. Michael’s Hospital or for other members of
my family. As well, the potential harms and benefits (if any) of participating in this research study have been
explained to me.
I have been told that I have not waived my legal rights nor released the investigators, sponsors, or involved
institutions from their legal and professional responsibilities. I know that I may ask now, or in the future, any
questions I have about the study. I have been told that records relating to me and my care will be kept
confidential and that no information will be disclosed without my permission unless required by law. I have
been given sufficient time to read the above information.
I consent to participate. I have been told I will be given a signed copy of this consent form.
Initial here if you agree to participate in study:
Initial here if you agree for us to observe your baby in this study:
Initial here if you agree to provide blood samples (baby’s and your own) for genetic testing: _____
Printed Name of Subject Subject’s Signature & Date
_________________________________ _________________________________
Printed Name & Title of Person who Signature & Date
Conducted Consent Discussion
105
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