Addiction apart from being a hygienic and
social problem is like a recurrent chronic brain disease, since
it has certain effects on brain function. Substance abuse leads
to special cellular change, as well as neurotransmitter and
chemical activities in neurons and receptors (1).
Two large studies have shown a higher
prevalence of psychiatric diseases among addicts, compared with
the common population (2, 3). The most common disorder in
treatment seeking opiate dependent patients is major depression
(lifetime 53.9%, current 23.8%)(4). However, in producing
addiction, in addition to psychopathologic factors, biologic,
social and environmental factors also have important roles (5).
In opioids abuse and dependency some
neurons, receptors, chemical transmitters and cerebral organs
play various roles. Opioid receptors in all parts of brain,
digestive system and other parts of autonomic system have been
discovered and it is not surprising if opioids cause alteration
in the functions of most body systems (6). These substances
have also significant effects on noradrenergic and dopaminergic
neurotransmitter systems (7).
Some studies have shown that opium
compounds exert their reinforcement and rewarding effects via
activating dopaminergic neurons in the tegmental area, which
extends toward cortex and limbic system (7). Naturally GABA has
an inhibitory effect on these neurons and morphine increases
dopamine via its inhibitory effect on GABA (5).
Long-term consumption of opioid compounds
alters the number and sensitivity of opioid receptors which are
the mediators of some drug dependency and quit effects (7).
Dependency occurs in long-term substance consumption, which is
accompanied by an increase in the sensitivity of dopaminergic,
cholinergic and serotoninergic neurons. It is possible that the
main mediator of drug quit is the effect of opioid substances
on noradrenergic neurons (7).
Drug quit after long-term consumption of
opioid compounds leads to symptoms called withdrawal syndrome.
This is the result of irritability in different parts of
central nervous system and similar to seizure in this aspect.
Even the electroencephalogram of drug quitters is affected and
in 50% of drug quitters significant changes in EEG have been
observed (8). In another study, quantitative
electroencephalographic (QEEG) of 90 patients with substance
abuse who had not used any substance for an average of 3 months
was investigated and a decrease in the intensity of Alpha and
Beta waves in comparison to normal state was observed (9).
Various therapeutic methods have been
suggested for drug quit, but none of them has led to complete
satisfaction of patients with regard to the control of
withdrawal symptoms during the detoxification period. Generally
the suggested protocols for drug quit are divided into two
groups: Conservative treatment with morphine agonists (e.g.
methadone) and treatment by using drugs without opioid
properties (e.g. clonidine)
Gabapentin (GBP) is a new anticonvulsant
drug used as an adjunctive therapy in partial seizures (10).
Based on experimental studies, GBP prevents maximal
electroshock convulsions and seizures due to electrical
kindling, pentylenetetrazol, thiosemicarbazide and isoniazid
(11). GBP has other uses also. In a study in mice, gabapentin
was found to control both anxious and convulsive symptoms of
alcohol withdrawal (12). Even alcohol-quit patients have
benefited from GBP and clomethiazole dosage has been decreased
in them (13). It is probable that the GBP effect is related to
an increase of GABA and decrease of glutamate system in the
central nervous system (14). Gabapentin as an analgesic has a
broad spectrum of efficacy in neuropathic pains (15). Based on
some studies, GBP increases the analgesic effect of morphine,
such that smaller doses of morphine are needed. This effect is
related to m receptors (16).
Moreover GBP has been recognized as a mood
stabilizer (17). The other study showed that gabapentin might
be a useful drug for the add-on treatment of bipolar patients
with incomplete response to other mood stabilizers (18).
However, studies on its efficacy in the treatment of anxiety
disorders or substance abuse are limited (17). In a study, GBP
has been introduced as an important adjuvant to the management
of opioid dependence in both acute detoxification as well as
stabilization phase (19). In another study, GBP has been found
as the first preemptive antihyperalgesic in the treatment of
hyperalgesia for opioid withdrawal syndrome (20).
In the present study, the efficacy of GBP
in the treatment of opioid dependent patients has been
investigated. For this purpose, the effect of GBP on opioid
withdrawal signs and symptoms and the psychiatric disorders and
EEG of patients during the detoxification period were studied.
Owing to ethical considerations, the action of gabapentin was
tested in add-on manner in addition to other usual medications
used in opioid withdrawal syndrome (clonidine, benzodiazepines,
NSAID, and diphenoxylate in case of need). There is no
pharmacological interference between these drugs and GBP. All
the patients gave an informed consent to participate in this
In this prospective clinical trial study,
71 opium-dependent participants (opium and other forms)
hospitalized in Kerman Psychiatric Hospital were selected
randomly and divided into two groups of G (gabapentin and usual
drug quit medication, N=35) and C (only usual drug quit
In admission, demographic features of
participants were recorded by using a general check list.
Females were excluded because of the low prevalence of
addiction among them and also in order to omit the probable
intervening effect of some drugs such as oral contraceptives
consumed by some women.
Two electroencephalograms, one at the
onset and one at the end of hospitalization period were
requested for all participants.
Group C received the usual medication for
drug quit [clonidine as the main drug (0.4-0.8 mg/d); NSAIDs as
analgesic (Ibuprofen, 1200mg/d); benzodiazepines (Lorazepam,
2-6 mg/d); tricyclic antidepressants (Amitriptyline, 25-75
mg/d); Promethazine 25-50 mg/d; Diphenoxylate PRN].
Group G in addition to the usual
medications, received 900 mg gabapentin daily, divided into
three doses, for 7-10 days.
All participants were evaluated by
SCL-90-R at the onset and end of the hospitalization period.
Electroencephalography was performed by
electroencephalogram (HELLIGE, Neuroscript, 8 channels) in
General check List
This was filled out by participants
themselves or the researcher and contained questions related to
job status ,type of job, monthly income, marital status,
educational level, number of sisters and brothers, birth order
in the family, type of the consumed narcotic, type of
consumption, the amount of daily use (g), the duration of
consumption, history of drug quit, tendency for using the new
drug for quitting, history of epilepsy, history of drug allergy
and the consumed drugs.
Check List for withdrawal signs and
This check List contains 13 signs
(yawning, lacrimation, rhinorrhea, sweating, tremor,
piloerection, restlessness, pupil size, anorexia, vomiting,
diarrhea, insomnia, and drug seeking) and 12 symptoms (muscle
cramp, palpitation, sneezing, pins and needle sensation, hot
and cold flashes, gooseflesh, feeling of sickness, stomachache,
muscular and skeletal pains, muscle twitching, feeling of
irritability, and craving) (21).
All participants were visited and given
daily scores for the above-mentioned signs and symptoms.
Symptom Check List-90-Revised (SCL-90-R)
SCL-90-R was used for evaluating the
psychiatric disorders at the time of admission and discharge.
With this test, nine aspects (somatic
complaints, obsession and compulsion, sensitivity to
interpersonal relations, depression, anxiety, aggressiveness,
phobia, paranoia, and psychosis) are measured and analyzed
based on the following indices: 1-General symptomatic index
(GSI), 2-Positive symptom of distress index (PSDI), 3-Positive
symptom total (PST).
SCL-90-R as a successful diagnostic method
is widely used through the world in patients with
alcohol/narcotic dependency, sexual disability, cancer, heart
failure, severe organic diseases and those who need
After data collection, they were analyzed
by SPSS and Stata v.7 computer softwares (power 80%, Confidence
Interval 95%). Nominal and ordinal variables were compared in
two groups (G and C) by Chi-square test or the Fisher Exact
Mean total score of withdrawal signs and
symptoms were compared by the Mann-Whitney U test. Wilcoxon
nonparametric test or paired sample test was used for comparing
the score of first and tenth days. One sample
Kulmogorov-Smirnov was used to test normal distribution. EEG
type in first and tenth days was evaluated in two groups by the
Mc-Nemar test. ANOVA, Repeated measures and Tukey Post-Hoc were
used for comparing variation of scores of withdrawal signs and
symptoms during detoxification period.
Results and Discussion
Mean age of group G (N=35) was
33.49±7.33 years and that of group C was 30.97±12
years and there was no significant difference between the two
Most participants in the two groups had
more than five brothers and sisters (p=0.86) and they were not
the first child in their family (p=0.77). There was no
significant difference between the two groups regarding their
monthly salary (p=0.80).
The consumed narcotic drugs in both groups
were heroine and opium, and the type of consumption was mostly
smoking. The amount of consumption was 2.36±1.85 g in
group G and 5.02±1.78 g in group C with no significant
difference (p=0.08). Most participants in both groups had been
addicted for more than one year.
Table 1 shows some of the demographic
features of participants.
There were only two significant
differences between the two groups which were in terms of the
marital and job status, this can not be explained from the
available data. But with all the other items, there was no
Withdrawal signs and symptoms during
the 10 days of treatment
I) Withdrawal signs
In group G scores of yawning
(9.03±4.7 times), lacrimation (3.94±4.2)
(p<0.01) and sweating (4.66±4.67) (p<0.05) were
significantly lower than those of group C (Table 2).
II) Withdrawal symptoms
In group G, scores of sneezing
(7.57±5.24), pins and needle sensation
(3.28±4.42), hot and cold flashes (5.6±5.97),
muscular and skeletal pains (6.97±6.55), muscle
twitching (4.28±5.64) (p<0.01), gooseflesh
(1.54±3.5), stomachache (3.97±5.16) (p<0.05),
were significantly lower than those of group C (Table 3).
In studying the results of withdrawal
signs and symptoms based on the check list (21), some signs
such as rhinorrhea, yawning, sweating and also some symptoms
such as sneezing, pins and needle sensation, hot and cold
flashes, gooseflesh, stomachache, muscular and skeletal pains,
and muscle twitching showed a significant decrease in the
gabapentin-treated group. With regards to diarrhea, vomiting,
muscle cramp and palpitation, with a power of <0.7 and an
increase in sample, a significant difference between the two
groups would be expected. Mean score of the withdrawal signs
and symptoms showed a decrease in both groups during the
process of treatment, but this decrease started earlier and
continued more rapidly in group G compared to group C. This
means that in group G, mean score of all days (except the tenth
day) were lower than those in group C. In group G, mean score
of the last three days was lower than the first day. This
finding was not observed in group C in none of the days.
A sudden increase in the mean score of the
withdrawal signs and symptoms on the second day is probably due
to the consumption of narcotics on the day of admission. As
figure 2 shows, there is no interaction between the symptoms
(power=0.3, if the number of samples were more, there would be
probably interaction between the first and second days).
There was a similar increase in the eighth
and ninth days, which is probably due to the start of
An overall study of the mean score of
withdrawal signs and symptoms during the ten days of
detoxification shows the efficacy of gabapentin in the drug
The results of previous studies on
experimental animals are evidence of the efficacy of gabapentin
in treating morphine withdrawal syndrome. Andrews et al.
carried out a study on the rewarding effect of morphine on two
distinct phases namely maintenance and development by the CPP
(Conditioned Place Preference) method. They found that
gabapentin-like compounds (gabapentin & pregabalin) blocked
the development of CPP to morphine and also blocked morphine's
effects on dopamine release. These compounds have no intrinsic
rewarding properties, and could have some therapeutic uses in
the treatment of opioid dependence (25). This shows that
gabapentin can decrease reinforcement and withdrawal signs via
blocking morphine's effect on dopamine release.
The study performed by Martinez-Raga
showed that gabapentin reduces symptomatic medications and had
a beneficial effect on the symptoms of heroin withdrawal (26).
Moreover it has been observed that
gabapentin is structurally similar to the inhibitory
neurotransmitter, gamaaminobutyric acid (GABA) (17), and the
action of this drug may be related to the enhanced potentiation
of (GABA) inhibitory neurotransmission (27). In other studies,
GBP efficacy on the opioid withdrawal syndrome have been
reported (19, 20).
Total score of withdrawal signs during the
10 days of treatment
As shown in figure 1, in group G, mean
score of withdrawal signs on the second day shows a significant
increase comparing to the first day and then it decreases and
only once it increases on the ninth day, comparing to the
eighth day. Mean score from the eighth day to the tenth day is
less than that of the first day.
In group C, there is an increase in the
mean score until the third day and then decreases on the fourth
day. From the fourth day till the seventh day it shows an
increase with a slight draft and decreases from the seventh
day. In this group, too, mean score of the last days is even a
little higher than the first day.
There are significant differences between
the two groups on the sixth day (P=0.023), seventh day (P=
0.0001), and eighth day (P=0.003). Interactions of signs in the
second day is significant [F(1)=4.071, P=0.04]. This fact shows
a significant difference between the two groups with regards to
the process of alterations on the first and second days (Figure
Mean total score of withdrawal symptoms
during the 10 days of treatment
Mean total score of withdrawal symptoms
shows a significant difference during the detoxification period
[F(4.588) =4.310, P=0.001]
As could be seen in the figure 2 regarding
the withdrawal symptoms, in both groups the second day shows an
increase comparing to the first day. In group C this increase
continues till the fifth day and then decreases until the
eighth day and again it shows a slight increase. While in group
G, decrease starts from the second day and only on the fifth
and seventh days show a little increase comparing with the
preceding days and the tenth day shows a higher score comparing
to the nineth day.
A whole comparison of two groups shows
lower mean scores for all the days in group G and there are
significant differences between the two groups on the fourth
day (P=0.046), fifth day (P=0.015), sixth day (P=0.003),
seventh day (P=0.035), eighth day (P=0.033) and the ninth day
(P=0.002). In group G mean score of the tenth day is lower than
the first day, while this was not true for group C.
The results of SCL-90-R in group G showed
a significant difference between the first and last days of
treatment in all scales. Aggressiveness, anxiety, depression,
sensitivity in terms of interpersonal relations, obsession and
compulsion, somatic complaints, phobia, paranoid thoughts and
psychosis on the first and tenth days showed significant
In group C, depression (P=0.0001),
sensitivity in terms of the interpersonal relations (P=0.001)
and paranoia (P=0.013) on the first and tenth days showed
In both groups, GSI and PSDI showed a
significant decrease in the last day of hospitalization,
compared to the first day. Only in group G, PST showed a
significant decrease in the tenth day compared to the first day
The effect of gabapentin on psychological
signs and SCL-90-R is significant in the gabapentin-treated
group. All disorders such as depression, aggressiveness,
sensitivity to interpersonal relations, phobia, paranoia,
obsession and compulsion, anxiety, psychosis, and somatic
complaints showed a significant decrease on the discharge day
comparing to the admission day. This finding should be
explained cautiously, because the two SCL-90-Rs were repeated
with an interval of ten days. On the other hand, the mean score
of SCL-90 in group C is higher than group G, but this
difference is not significant. According to Letterman et al.,
gabapentin is highly effective in the treatment of some
psychiatric disorders such as bipolar disorders, anxiety,
behavioral problems and substance-abuse. Moreover, because of
having very limited side effects, no need for therapeutic drug
monitoring and minimal pharmacological interactions, it is a
very useful drug indeed (17).
Cabras et al. have performed a study about
the efficacy, tolerability and safety of gabapentin as an
adjunctive drug in the treatment of schizophrenic patients with
manic and hypomanic signs. They found that gabapentin is highly
effective in treating mania and hypomania in patients with
bipolar disorders and schizophrenia. They introduced gabapentin
as a well-tolerated and rapidly acting antimanic drug (28).
The results of all these studies as well
as the results of the present study suggest that gabapentin, as
a drug which causes no dependency, could be used for decreasing
the withdrawal syndrome in opioid-dependency and also in
treating psychiatric disorders.
In both groups no significant difference
between the first and tenth days were seen in the
electroencephalogram indices such as wave activity (normal,
slight, moderate, severe), CPS (Cycle Per Second), wave type
(alpha, beta, delta, and theta) and epileptic tendency (normal,
low, high). There was also no significant difference in these
indices between the two groups, but there was a significant
difference on the first and tenth days in terms of CPS in group
Mattia et al. performed a study on
patients with focal epilepsy who were resistant to other
antiepileptic drugs. They used gabapentin in these patients and
observed only an increase in theta relative power. In their
study, gabapentin had no effect on ictal and interictal EEG,
and it only caused a reduction in seizure occurrence (29). Also
in the present study, there was no significant difference
between the two groups with regards to the EEG indices such as
the rate of abnormal waves, type of waves, CPS and also
It should be mentioned that delta waves
are pathologic and theta waves are seen naturally in the
partial cortex of people less than 15 years old. Beta waves may
be present in case of using some drugs. Therefore, any
discussion about wave types in our patients before omitting the
effective factors is not possible. On the other hand, there was
no convulsive disorder in our patients, and this could be the
reason of seeing no difference between EEG indices in the two
The exact mechanism of action of
gabapentin is not well known, but its significant efficacy in
the treatment of withdrawal signs and symptoms and psychiatric
disorders during detoxification period can suggest it as one of
the main choices in treating the opioid withdrawal syndrome.
Further physiological and controlled studies are recommended to
determine the potential effect of gabapentin during the
Kerman Azad University and Shaheed
Beheshti Hospital staffs are acknowledged for their assistance.