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

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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

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