This study was a randomized controlled trial, conducted in accordance with the Declaration of Helsinki and the protocol was approved by the Ethics Committee of the hospital (13/CE/15, n.437/1), in accordance with the Consolidated Standards of Reporting Trials (CONSORT) and Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) guidelines for designing and reporting controlled trials [23,24]. All participants signed the informed consent form before participation in the study.
- Inclusion criteria for the study were the following: female subjects; age more or equal 18 years; diagnosis of non-metastatic breast cancer; in treatment with hormone replacement therapy; ECOG Performance Status  equal to "0-1"; sleep difficulties arising after the start of breast cancer treatment; onset of sleep difficulties in the 3 months before; absence of restless legs syndrome; absence of sleep apnea; availability for 1 weekly meeting for 8 consecutive weeks; if being treated for insomnia, the sleep therapy must have been stable for at least 30 days; willingness not to change therapies and dosages of treatments for sleep disorders and / or hot flashes for the duration of the study, unless otherwise indicated by the doctor; adherence to the study by signing the Informed Consent Form (ICF).
- Exclusion criteria were: previous acupuncture treatment in the last 12 months; presence of lymphedema; thrombocytopenia (<50000); neutrophils <1000; presence of relevant comorbidity; history of other neoplasms in the last 10 years; presence of important psychiatric syndromes or cognitive disorders; bleeding tendency; participation in other studies of the oncology division.
Definition of insomnia. We have divided insomnia into 4 macro-areas. A first form, initial insomnia, related to the difficulty of falling asleep. A second is median insomnia which occurs in both the non-REM and REM phases. A third, terminal insomnia, linked to an early morning awakening. Finally, insomnia due to light and unstable sleep. The proposed definition is dictated by the need to combine the personalization of the intervention (multiplicity) with the replicability of the study (simplification). The resulting groups are sufficiently homogeneous within them, but differentiated with respect to the specific problem of the patient.
- The Initial Insomnia. In our hypothesis, the initial insomnia is linked, according to the schemes of traditional Chinese medicine, to different imbalances. The first consists of a deficit Yang Ming, in particular of the meridian of the large intestine which is responsible, among its various functional correspondences, for the functioning of the intestinal transit and the secretion of serotonin through which it partly controls the mood and the initial phase of sleep through an effect on Tsue Yin (Meridians of Pericardium and Liver, responsible for the ortho-sympathetic tone) and the Shao Yang (Meridians of Triple Burner and Gallbladder, responsible for the parasympathetic tone). A deficit of the meridian of the large intestine, reducing the secretion of serotonin, would induce an increase in the ortho-sympathetic tone and reduce the parasympathetic tone, preventing the normal relaxation of the striated muscles that accompanies the first phases of sleep. A second type of Initial Insomnia is always linked to a deficit of the meridian of the large intestine, but also to an excess of the liver meridian, the latter would in turn induce an excess of the heart meridian with a mental hyperactivation and an inability to abandon oneself to rest. Often the two conditions coexist. The third type of initial insomnia is due to a primary excess of the Shao Yang which induces motor restlessness and is reflected secondarily, given its action on the heart meridian in a mental Hyperactivity.
- The Median Insomnia. We have 2 types of median insomnia, that is, linked to awakening after a first phase of deep sleep. The first is linked to an awakening that takes place in a non-REM phase of sleep and is always linked to a dysfunction of the meridian of the large intestine but whose prevailing effects are those of overstressing the Shao Yang inducing an anxious awakening, also characterized by a state of mental confusion. The second is linked to an awakening that occurs in a REM sleep phase and is always linked to a primitive or secondary excess of the Shao Yin group and in particular of its heart meridian that causes an awakening in a clear mental state.
- The Terminal Insomnia. It is what we define as an early awakening compared to the patient's previous habits and which does not allow the achievement of an adequate satisfaction of the individual needs for sleep. From the point of view of traditional Chinese medicine this is mainly due to a hyperactivity of the Tai Yin energy group which suppresses the activity of the Shao Yin energy group (Kidney and Heart meridians), responsible among other things, in our interpretation, for the synthesis of a neuromodulator important in maintaining the sleep, the Gamma-Aminobutyric acid.
- The Light and Unstable Sleep. In the complex relationship of energetic groups of meridians, this form of insomnia is related to an imbalance of three groups: the Tai Yang responsible of a insufficient GABA synthesis that enhances the central sympathetic tone due to Shao Yang (Heart meridian) and suppress the synthesis of serotonin, controlled by the Yang Ming (Large intestine meridian).
Enrollment. The study was presented to Oncology DH patients who met the inclusion criteria. If a patient agreed to participate, a researcher checked for eligibility criteria. All confirmed patients underwent a first diagnostic visit by a medical doctor acupuncturist for an anamnestic examination of the energy imbalances that can be configured in a different way in relation to the constitutional type according to traditional acupuncture diagnosis (Tai Yin, Yang Ming, Shao Yin, tai Yang, shao Yang and tsue Yin) and according to the sleep disorder presented (i.e.: initial calm and agitated insomnia, median insomnia with lucid awakening, median insomnia with confused awakening). For each patient the acupuncturist (F.J.) sets an energy diagnosis, according to the ethical-professional principles of the Italian Acupuncture Association, based on what emerged during an in-depth individual interview. Once the energy diagnosis was made, patient signed the ICF, and agreed a weekly schedule of appointments for a duration of 8 weeks. During the same visit, the patient filled in the questionnaires for the detection of the variables under study.
After ICF and baseline assessment the patients were randomized to either acupuncture group (AG) or control group (CG) using a block allocation of four. The randomization was performed using a computer-generated list of random numbers, with a block size of four provided by an investigator not involved in the trial. The sealed envelopes numbered in ascending sequence contained the allocation for each patient.
Acupuncture group (AG)
At each meeting, the medical doctor acupuncturist, before placing the needles, visited the patient by detecting the radial pulse and examining the tongue (for traditional Chinese medicine they are an integral part of the diagnosis, together with the medical history). Patients will have been applied 8-20 disposable needles. The patients were treated with acupuncture in relation to the energy picture presented. The positioning of the needles was done according to the evaluation of the type of insomnia according to the following scheme:
1- Initial Insomnia, first type, was treated with: LI11, St25, St36, St43, St44, REN12, P6, GB34, GB38.
2- Initial Insomnia, second type, was treated with: H3, H7, P6, REN 17, Ki6, Bl60, Li11, ST36, ST43.
3- Initial Insomnia, third type, was treated in two steps. 1st: Ren5, HE3, Ki3, TB5, Gb38, Bl59, Bl60 and 2nd: Gb34, Gb38, He3, Ki3, Gv3, Gv5.
4-Median Insomnia, with Awakening in non-REM phase: P1, P7, Ren17, Gb34, Gb38, Gb43, Li11, St25, St36, St 43, St44, Ren12
5- Median Insomnia, with Awakening in REM phase: He3, He7, Ki6, Bl60, Lv3 Ren5.
6- Terminal Insomnia: Ki6, Ren5, St36, St44, Lu2, Lu5, He3, He5.
7- Light and Unstable Sleep: Bl59, Bl60, Ren17, Ren3, He3, He5.
All the points mentioned are bilateral except for the points marked with the initials DU and REN which are respectively on the posterior and anterior midline of the trunk. The details on the anatomical location of these points are reported in Table 1.
Table 1. Description of acupuncture pressure points
Great Stream, Ki 3
On the medial aspect of the foot, posterior to the medial malleolus, in the depression between the tip of the medial malleolus and tendo calcaneus.
Shining Sea, Ki6
On the medial aspect of the foot, in the depression below the tip of the medial malleolus.
Pool at the Crook, Li11
With the elbow flexed, the point is on the lateral end of the transverse cubital crease, at midpoint between LU 5 and the lateral epicondyle of the humerus.
Middle Epigastrium, Ren12
On the anterior median line of the upper abdomen, 4.0 cun above the umbilicus.
Chest Center, Ren17
On the anterior median line of the chest, at the level of the 4th intercostal space, at the midpoint between the two nipples.
Inner Gate, P6
On the palmar aspect of the forearm, 2 cun above the transverse crease of the wrist, on the line connecting PC 3 and PC 7, between the tendons of m. palmaris longus and m. flexor carpi radialis.
Hill Spring, Gb34
On the lateral aspect of the lower leg, in the depression anterior and inferior to the head of the fibula.
Yang Aid, Gb38
On the lateral aspect of the lower leg, 4 cun above the tip of the external malleolus, slightly anterior to the anterior border of the fibula.
Celestial Pivot, St25
On the middle of the abdomen, 2 cun lateral to the umbilicus.
Leg Three Miles, St36
On the anterior aspect of the lower leg, 3 cun below ST 35, one finger-breadth (middle finger) from the anterior crest of the tibia.
Sunken Valley, St43
On the dorsum of the foot, in the depression distal to the junction of the second and third metatarsal bones.
Inner Courtyard, St44
On the dorsum of the foot, proximal to the web margin between the second and third metatarsal toes, at the junction of the red and white skin.
Lesser Sea, He3
When the elbow is flexed, the point is at the midpoint of the line connecting the medial end of the transverse cubital crease and the medial epicondyle of the humerus.
Connecting Interior, He5
On the palmar aspect of the forearm, the point is on the radial side of the tendon m. flexor carpi ulnaris, 1.0 cun above the transverse crease of the wrist.
Spirit Gate, He7
On the wrist, at the ulnar end of the transverse crease of the writs, in the depression on the radial side of the tendon m. flexor carpi ulnaris.
Instep Yang, Bl59
On the posterior aspect of the lower leg, behind the external malleolus, 3 cun directly above UB 60.
Kunlun Mountains, Bl60
On the foot, behind the external malleolus, in the depression between the tip of the external malleolus and tendo calcaneus.
Lumbar Yang Gate, Du3
On the lumbar region, on the posterior median line, in the depression below the spinous process of the 4th lumbar vertebra.
Suspended Pivot, Du5
On the lumbar region, on the posterior median line, in the depression below the spinous process of the 1st lumbar vertebra.
Great Surge, Lv3
On the dorsum of the foot, in the depression proximal to the 1st metatarsal space.
The acupuncture was performed for 8 sessions during a 8-week period (once weekly).
Sterilized disposable bimetallic needles (copper handle and steel blade) (Hwato brand, in compliance with all European and Italian regulations) measuring 40mm x 0.32mm were inserted, forming a 90-degree angle with the skin surface and rotated anti-clockwise.
The acupuncture points were identified and chosen after the interpretation of the energy imbalances present in the patient.
Acupuncture is a safety form of healthcare with a low relative risk. Since it is not an entirely risk-free medical procedure, it should be administered by practitioners with the proper training who follow accepted guidelines of practice. To mitigate the “acupuncturist effect” we had established the rotation of acupuncturists in the treatment of the same patient.
The acupuncture treatment will be carried out exclusively by 3 medical doctors qualified by the Italian Association of Acupuncture (F.J., M.C., P. C.) with more than 15-year of acupuncture experience, who participate in the study on a voluntary basis.
Before the start of the study, 6 in-depth and comparison meetings were held between the 3 acupuncturists to guarantee the uniformity of the application of the treatment. Before each session, the acupuncturists confronted each other to decide on a shared treatment. Every week, on Wednesday afternoon, meetings were held between the whole team to monitor the progress of the treatment.
Control group (CG)
Patients assigned to the control group were received once a week, for 8 weeks, by an oncologist. Received individually in an outpatient room and interviewed about the state of health and the undesirable effects of the therapies.
The main study outcome was the severity of insomnia measured by ISI.
-The Insomnia Severity Index (ISI) [14,26] is a brief self-report questionnaire to measure the patient’s perception of severity insomnia. The questionnaire measures characteristics and consequences of insomnia in the last 2 weeks. The items’ content corresponds in part to the diagnostic criteria of the insomnia in DSM-5. The ISI is composed of seven items that evaluate (1) the severity of sleep-onset, (2) difficulties in sleep maintenance, (3) early morning awakening problems, (4) dissatisfaction with current sleep pattern, (5) interference with daily functioning, (6) noticeability of impairment attributed to the sleep problem, and (7) level of distress caused by the sleep problem. Each of these items is rated on a 0-4 scale and the total score ranges from 0 to 28. ISI has frequently been used as measure of outcome.
The severity of insomnia is assessed on the basis of the reported score, as below:
0- 7 = absence of clinically significant insomnia;
8-14 = insomnia below the clinical threshold;
15-21 = clinical insomnia of moderate severity;
22-28 = severe clinical insomnia.
Patients that reported ISI score>14 are probable cases affected by clinical insomnia. In this study, the internal consistency of the scale was α =0.77.
- The Sleep Disturbance Questionnaire (SDQ) [27,28] is a 12-item questionnaire to measure subjective experiences of usual sleep habits and sleep difficulties. The items are grouped into four factors which reflect physiological, cognitive and behavioral aspects. Each item is answered on a 5-point scale (“1=never true,” “2=seldom true,” “3=sometimes true,” “4=often true,” “5=very often true”). It is possible to obtain 4 distinct scores: (1) a measure of restlessness/agitation or "Physical tension", (2) a measure of "Inadequate sleep pattern", (3) a measure of “Cognitive vigilance” or difficulty in falling asleep, and (4) a measure of "Effort to sleep". A measure of "Mental overactivity" derives from the sum of the scores in “Difficulty in falling asleep” and “Effort to sleep”. Subjects are asked to rate items in relation to typical nights when they do not sleep well, and to specify if each problem happened at least three nights per week for at least 3 months. In this study, the internal consistency of the scale was α =0.70.
The questionnaires were filled out for both groups at baseline and 8 weeks later.
Sociodemographic and clinical information, as the presence of as specific symptoms (i.e.: repetitive leg movements), were also collected.
The sample size calculation was based on the results of a pilot study on sleep quality (mean score in "absence of chronic insomnia" = 9.52; standard deviation = 3.16; mean score in "presence of chronic insomnia" = 12.05; standard deviation = 2.03). Intending to compare the differences between post-treatment mean and mean at baseline (change method), to calculate the number of subjects to be allocated to each group, setting alpha = 0.05 (two-sided) and power = 90%, 56 patients were examined and equally assigned to each group. Considering a 30% exclusion, 72 patients will be invited to participate in the study.
Data were presented as mean and standard deviation (SD) or frequency (n) and percentage (%), to describe demographic and clinical characteristics of the whole sample and separately for acupuncture and control group.
The difference in the baseline characteristics between the acupuncture and control groups was determined with the t-test or Chi-square test. Differences between baseline and follow up measures for variables in study used mean, 95% confidence intervals (CIs). The change between baseline and follow up was calculated as the difference between the two measures (delta).
For the purpose of analysis, we divided into two categories the SDQ domain scores at the median value (0=less than or equal median value; 1= higher than median value); delta scores (0=no improvement if delta score <1; 1=improvement, delta score>0).
Multivariate logistic regression models were built to assess the association between improvement in insomnia (compared to stability/deterioration) and all variables resulted associates at the univariate analyses, while simultaneously adjusting for possible confounding factors as age, previous use of CAM (0= no; 1= yes), years of school (0= less than 13 vs 1= 13 or more).
The internal consistency of the scales was estimated with a Cronbach alpha coefficient by the item-total correlations.
All statistical analyses have been performed using STATA, version 11.0 (StataCorp, College Station, Tex).
Seventy-two breast cancer females aged 26-81 years (mean = 53.59; standard deviation, SD = 11.06) volunteered for this study by responding to an invitation to participate if the inclusion criteria were met.
After a preliminary visit with two medical doctor acupuncturists, to assess the characteristics of the sleep difficulties, 14 women were excluded. Seven for important comorbidities no-cancer related, 4 for the minor difficulties in sleep, 3 for not being available for a weekly treatment in the month after.
Fifty-eight breast cancer women with ascertained sleep difficulties were randomized into two groups (AG and CG).