Lupine Publishers | Scholarly Journal Of Psychology And Behavioral Sciences
Introduction
Addiction is defined as
a chronic relapsing neurobiological brain disease. The rate of drug addiction
in Egypt is twice the global rate so working on the development of new
preventive and treatment modalities is crucial. One of the most prevalent
features of opioid addiction is the tendency to relapse on the drug even weeks,
months or years after stoppage of opioid use. Exposures to stress or
conditioned cues related to heroin abuse are distinct conditions that induce
relapse. Craving (the intense desire to take a drug) is a central aspect of
drug addiction and a contributing factor in relapse after period of abstinence.
The National Institute on Drug Abuse reports that 40 to 60 % of people treated
for substance use disorders relapse. For heroin, the numbers tend to be
approximately twice that rate, 59% of which occurred within 1 week of discharge
[1].
Aim of the Work
The aim of this work was
to assess the efficacy of transcranial magnetic stimulation (TMS) and cranial
electrotherapy stimulation (CES) on craving of heroin use disorder.
Subjects and Methods
The design of the
current research was randomized controlled clinical trial to assess the
effectiveness and outcome of Transcranial Magnetic Stimulation (TMS) and
Cranial Electrotherapy Stimulation (CES) on heroin abuse craving. This study
was done in Neuropsychiatry Department and Psychiatry and Neurology Center,
Tanta University over a period of 27 months started from June 2018 through
September 2020 on eighty patients who fulfilled the diagnostic criteria of
heroin use disorder according to DSM-5.
Inclusion criteria
consisted of heroin abusers aged 18-30 years. Exclusion criteria included
patients with current medications which may alter EEG activity as
anticonvulsants or patients with history of any neurological disorder that
would result in abnormal EEG activity or current substance abuse other than
heroin and the presence of implanted devices as cardiac pacemaker. Patients
were randomized either to receive active TMS (20 patients) versus sham TMS (20
patients) or to receive active CES (20 patients) versus sham CES (20 patients).
All patients were subjected to history taking included personal or drug
history, systemic or mental state examination and urine drug screen. Craving
was induced by cues of heroin blocks or pictures before applying the
questionnaire or performing the EEG. Craving was assessed objectively by EEG or
subjectively by BSCS at base line before starting TMS or CES, then at the next
day after completion of 10 session of TMS or CES and after one or three months
follow up.
For EEG recordings,
participants were asked to close their eyes and to avoid mental activities as
well as movements or muscular contractions during the recordings. EEG was
recorded with Neurofax nihon Kohden QP-110 AK from scalp locations placed
according to 10-20 international system. Resting EEG was recorded for 5 min to
identify the baseline background activity of each patient. The EEG was
digitized, and fast Fourier transformation (FFT) was performed. Fourier analysis
converts a signal from its original domain (often space or time) to a
representation in the frequency domain and vice versa. To calculate EEG power,
the frequency spectrum was divided into 0.2 Hz bands and collapsed into EEG
frequency bands of delta (1- 3.9 Hz), theta (4.0-7.9 Hz), alpha (8.0-12.9 Hz)
and beta (13.0- 30 Hz). Each power value represented 5 seconds, and we analyzed
30 seconds of recording per case. Then we designated these power values as
average percentages of total power. These were usually called delta, theta,
alpha, and beta power ratios. Then, we exposed each patient to cue-induced
craving pictures or previous heroin use situations according to each patient`s
history of intake for recording a baseline EEG. Instructions were to sit relaxed,
still and to carefully attend to the cues without employing distracting
thoughts. The frequency domain analysis was performed using the Fast Fourier
Transform (FFT) algorithm to calculate absolute (μV2/Hz) power density,
relative (%) power density and mean frequency (Hz) within each of the
sub-bands. The absolute power of a band is the integral of all of the power
values within its frequency range. Relative power (RP) indices for each band
were derived by expressing absolute power in each frequency band as a percent
of the absolute power (AP) summed over the four frequency bands. Absolute power
was log transformed (log x) and, relative power variables were transformed by
log {x/1-x} in order to normalize the distribution of the data. EEG frequency
(Hz) indices were found to be normally distributed and thus did not require
transformation [2]. The BSCS is a self-report instrument to assess craving for
heroin abuse over a 24-hour period. Patients were asked to complete a scale,
rating the intensity, frequency and length of their cravings. Ratings were then
scored on a scale of 0 to 12 (0 meaning no cravings; 12 meaning the patient was
experiencing severe cravings) [3].
TMS Protocol
Group I patients (40
patients) received TMS sessions after one week of heroin abstinence. Before
starting the study, individual TMS motor thresholds were determined for each
participant. Individual motor threshold (MT) was determined similar to the
method described [4]. TMS intensity was varied using an ascending staircase procedure
and the motor evoked potential (MEP) of the abductor pollicis brevis muscle was
assessed. High Frequency rTMS (HF rTMS) at 10 Hz (24 trains, 5 s per train, 25
s intertraininterval, i.e. 1200 pulses, 90% MT) was applied via a figure-eight
coil with an outer winding of 70 mm connected to a Magstim Rapid-2 stimulator
[5] targeting the left DLPFC. The duration of each session (real or sham TMS)
will be 20 minutes for 5 days per week for 2 weeks, so each patient received 10
sessions. Sham stimulation was administrated at the same location, strength and
frequency with the coil angled 45o away from the skull. This method reproduced
sound and some somatic sensation (vibration and contraction of scalp muscles)
that resemble active stimulation while generating intracerebral voltage
approximately 1/3 that of active TMS stimulation [6].
CES Protocol
Group II patients (40
patients) received CES sessions after one week of heroin abstinence.
Twenty-minute (5 days per week for 2 weeks) application of 10 sessions of CES
using alphastim technology (Electromedical products international Inc., Mineral
wells, Texas; www.alpha-stim.com ). Earclips electrodes were moistened with a
conducting solution and attached to the earlobes. Current levels of the CES
device (which range from 100 to 500 microamperes) were adjusted following
manufacture recommendations to a comfortable level just below where vertigo is
experienced. Sham CES was administrated at same location, strength and
frequency but with CES device turned on and off. The collected data were
organized, tabulated and statistically analyzed using SPSS version 19
(Statistical Package for Social Studies) created by IBM. There were descriptive
and comparative types, where quantitative data were summarized as mean and standard
deviations while qualitative data were summarized as numbers and percentages. A
comparison was made using Paired student test (t - test) in case of two groups
quantitative data. The chi-square test(X2) and Fisher exact test (FET) were
used for qualitative data. Differences were considered significant if the P
value was 0.05 or less. The study’s protocol was approved by The Research
Ethics Committee and Quality Assurance Unit, Faculty of Medicine, Tanta
University. Participations were voluntary, informed consents were obtained from
all included patients and the possible risks were clarified.
Results
The current study showed
that the mean age of patients was (24.8 ± 3.8) without significant difference
among different study groups (Table 1). The participants in this study were all
male (100%). Five heroin abuser females refused to participate in our study
secondary to fear and stigma despite maintained privacy and confidentiality of
the data. According to the marital status of the participants, half of them
(50%) were single. Technical educational level was the commonest among
participants. Most of participants were in the middle and low social class
levels. According to the family characters, most families were of extended
type. Tobacco abuse was the commonest substance of abuse by families followed
by cannabis and heroin. Antisocial personality disorder represented the main
personality disorder among participants. Peer influence (62.5%) and curiosity
represented the main causes of heroin abuse between study group’s patients.
According to addiction severity index, drug abuse was considered the main
problem among this study participants followed by employment problems.
Intravenous injection (63.7%) of heroin was the commonest form of heroin intake
among all participants. There was no significance regarding the daily dose of
heroin or the duration of abuse among the study groups. The current study
showed no significant difference regarding the BSCS baseline scores between all
study groups before performing any TMS or CES sessions. The current study
showed significant decrease in BSCS values after (10 sessions of active TMS or
active CES) and after one month and three months follow up with least values in
active TMS group which indicate the least craving in active TMS group (Tables 2
& 3). After three months follow up there was slight increase in BSCS values
which indicate more heroin craving. Despite these observed increase in BSCS
values with follow up, the active TMS group subjects showed the least increase
among all participants and still had significant difference with baseline
craving (Figure 1). Power ratios are an index of EEG power reflecting changes
in the balance of EEG power by frequency band. The current study showed no
significant difference regarding mean log transformed beta band power at
baseline before performing any TMS or CES sessions (Table 3). The current study
showed significant decrease in mean log transformed beta band power values
(after 10 sessions TMS or CES) and after one month follow up with least values
in active TMS group which indicate less craving in this group (Figure 2). This
study showed no significant difference between mean baseline beta band
frequencies at F3 and F4 among study groups with higher values at F3 than F4
which indicated relative greater activation of left frontal hemisphere than the
right one. The mean beta band frequency in active TMS group after performing 10
sessions TMS or after one month follow up at F3 was lower than F4 which
correlated with the effectiveness of active TMS in modulation of brain activity
in left prefrontal region (Table 4).
Discussion
Craving for heroin can
be described as a powerful urge to use heroin again. Patients with craving have
an intense desire to use heroin accompanied by vivid day dreaming about using
heroin or difficulty in focusing on anything other than getting it. The current
study showed that the mean age of patients was (24.8 ± 3.8) without
significance among different study groups. The participants in this study were
all male (100%). The higher ratio in heroin abuse in males may be attributable
to the more freedom that males can obtain in our society and the easier ways to
obtain the drugs than females. In Egypt, females still have lower prevalence
rates than men due to culture effect. The involvement of 100% male gender in
this research may provide an advantage of avoidance the genderassociated
differences in craving as a result of hormonal changes throughout the menstrual
cycle but it also lacking the advantage of gender difference studying [7]. The
current study showed no significance regarding the BSCS baseline measures
between all study groups but after 10 sessions TMS or CES these values were
decreased with significant difference in active TMS and CES groups which
indicate significant reduction of heroin craving but the maximum decrease was
noticed in subjects who received active TMS sessions than active CES. So, both
active TMS and active CES were significantly effective in reducing heroin
craving but TMS was significantly more effective than CES. After three months
follow up there was slight increase in BSCS values which indicate more heroin
craving. Despite these observed increase in BSCS values with follow up, the
active TMS group subjects showed the least increase among all participants and
still had significant difference with baseline craving.
This downward shift of
BSCS values after 10 sessions TMS or CES confirm the acute efficacy of these
maneuvers to decrease craving in heroin use disorder patients especially in
active TMS group but the observed slight increase of BSCS scores (which
indicate more heroin craving) especially after three months follow up may
confirm the need for further booster TMS or CES sessions throughout a
longitudinal six month protocol. A prominent factor for the increase of craving
within three months follow up is the presence of environmental drug cues.
Continuous changes in reward and memory brain circuitry which are related to
drug dependence result in high sensitivity to drug-linked cues during
abstinence [8]. Furthermore, impairment in the regulation of the
hypothalamic-pituitary-adrenal axis caused by opioid dependence is correlated
to enhanced sensitivity to stressors during abstinence. Such abstinence related
impairment of reward and stress response systems may explain the subjective
experiences reported by study participants during abstinence and the constant
desire for drugs even in case patients are in residence and living far from
social, drug use-related, environmental stimuli of craving. Shi et al study
corroborated our findings regarding a significant reduction of heroin craving
among participants after one month follow up after abstinence [9]. On the
contrary, Fathi et al declared a reduction of heroin craving for one month
follow up but without statistical significance. Such a difference may arise
from the different psychometric test used, small sample size and absence of
drug cues [10].
According to Jack et al
in a systematic review and meta-analysis regarding effect of rTMS on craving in
substance dependence patients, rTMS revealed a significant anti-craving effect
of the left DLPFC in patients with substance dependence. Excitatory rTMS
targeting left DLPFC shows promise in reducing both craving and substance
consumption, which may be a result of dopamine release and/or activation of the
dorsal PFC executive functioning system. However, this effect was limited in
duration, as indicated by a nonsignificant treatment effect at follow-up [11].
CES may produce its effect on decreasing heroin craving with ear-clip
electrodes through achieving parasympathetic nervous system dominance by
stimulating the auricular branch of the vagus nerve. Withdrawal symptoms
including craving are basically manifestations of sympathetic nervous system
over activity. CES also improves anxiety and frequent insomnia which are common
symptoms in the early stage of recovery from heroin and these symptoms are the main
precursor for relapse. In our current study, these effects appear to be session
linked with increased craving or desire to take a heroin again after stoppage
of CES sessions especially with continued follow up for three months. The
current study showed that the mean log transformed beta band power values at
base line had no significant difference between the study groups but after 10
sessions TMS or CES these values were decreased with significant difference in
both active TMS or active CES study groups which indicate less craving but the
maximum decrease was noticed in subjects who received active TMS sessions. So,
both active TMS and active CES were significantly effective in reducing heroin
craving but TMS was significantly more effective than CES. Active TMS group
showed significant decrease of absolute beta band power values from baseline to
10 sessions application or after one or three months follow up. These results
were in agreement with Jurgen et al who showed that absolute beta power
significantly decreased with rTMS sessions but this study results were related
only to the acute effects of TMS without further follow up. Jurgen reported
that absolute beta band power was significantly decreased more with active TMS
versus sham TMS. He postulated that active TMS session might mimic craving
action on brain reward functions producing an increase of dopamine release with
further cognitive inhibitory control mechanism [12].
Our study showed no
significant difference between mean baseline beta band frequencies at F3 and F4
among study groups with higher values at F3 than F4 which indicated relative
greater activation of left frontal hemisphere than the right one. The mean beta
band frequency in active TMS group after performing 10 sessions TMS and after one
and three months follow up at F3 was lower than F4 which correlated with the
effectiveness of active TMS in modulation of brain activity in left prefrontal
region. We reported that the left frontal hemisphere had greater activation
than the right hemisphere after cue induction and therefor the choice of left
DLPFC for neuromodulation of substance induced craving is an optimum location
to manipulate. Our findings were in agreement [3,5].
Conclusion
Transcranial magnetic
stimulation (TMS) and cranial electrotherapy stimulation (CES) are effective
non-invasive treatment modalities for the acute reduction of heroin craving
with significant reduction of heroin craving through three months after heroin abstinence.
So, TMS or CES are considered valuable noninvasive devices to overcome the
risky period of heroin craving especially after one month of heroin abstinence.
So, TMS or CES represented new effective method for relapse prevention in
heroin use disorder. Active TMS shows significant difference for reduction of
heroin craving than sham TMS. Active TMS is more effective treatment modality
for reduction of heroin craving than active CES. The observed slight increase
of BSCS scores or the beta band power readings (which indicate more heroin
craving) especially after three months follow up may confirm the need for
further booster TMS or CES sessions throughout a longitudinal six-month
protocol. Despite this observed slight increase of BSCS scores or the beta band
power within three months after abstinence, the BSCS scores or the beta band
power still have significant difference than the baseline readings. The left
frontal hemisphere has greater activation than the right hemisphere after cue
induction. Therefore, the choice of left DLPFC for neuromodulation of substance
induced craving is an optimum location to manipulate
Recommendations
We recommend the use of
rTMS or CES as non-invasive treatment options for acute reduction of heroin
craving which provide improvement in the adherence to the recovery programs and
prevention of relapse. We recommend the use of TMS for acute reduction of
heroin craving as a superior efficient tool than CES. However, CES provides an
easily accessible home treatment option for reduction of heroin craving
especially if TMS apparatus is not available or if there are any
contraindications of TMS use. We recommend the need to adopt a uniform
prolonged treatment protocol and optimize the number of rTMS sessions in
relation to treatment of patients with heroin use disorder during the whole
abstinence months. We recommend the restrict prevention of heroin abuse
patients during the abstinence period from exposure to heroin cues which induce
craving that represents an important cause for heroin relapse. Violent craving
can erupt suddenly into consciousness after exposure to drug cues, acting as a
persistent cause for relapse. We recommend the presence of comprehensive
effective rehabilitation program for six months for heroin abusers till
complete normalization of brain neurobiological changes associated with heroin
abuse.
Limitations
The need for further
studies with longer follows up duration (six months) which may offer a more
informative data about neurobiological changes for the whole abstinence period
in heroin use disorder. The need for further studies to identify the
neurobiological changes for heroin craving in females for proper assessment of
the gender difference.
Declaration
Ethics approval and consent to participate section
- The manuscript was
approved from The Research Ethics Committee and Quality Assurance Unit, Faculty
of Medicine, Tanta University.
- The study’s protocol
had permitted by The Research Ethics Committee and Quality Assurance Unit,
Faculty of Medicine, Tanta University. Participations were voluntary, informed
consents were approved by all participants’’ guardian and any possible risks
were clarified.
Consent of publication: Not applicable.
Competing interests: All authors disclose that they have no competing interests
related to the study.
Availability of data and materials: The datasets used and/ or analyzed during
the current study are available from the corresponding author on reasonable
request.
Authors Contributions:
MSK: participated in the
study’s design, patients’ selection, statistical analysis, data analysis,
references collection, manuscript writing and revision and final approval, WSB:
participated in the study’s design, patients’ selection, EEG interpretation,
statistical analysis, data analysis, manuscript writing, revision and final
approval, AAH: participated in patients’ assessment and inclusion, data
analysis, psychometric scale analysis, statistical analysis, references
collection, manuscript writing, revision and final approval, GTS: participated
in the study’s design, patients’ selection, and evaluation, data analysis,
references collection. EAG: participated in study’s idea and design, patients’
assessment and inclusion, data analysis, references collection, manuscript writing,
revision and final approval.
