Mohamad et al.

Harm Reduction Journal 2010, 7:30

[Link]

RESEARCH Open Access

Better retention of Malaysian opiate dependents

treated with high dose methadone in methadone
maintenance therapy
Nasir Mohamad1,2*†, Nor Hidayah Abu Bakar1†, Nurfadhlina Musa1, Nazila Talib1, Rusli Ismail1†

Abstract
Background: Methadone is a synthetic opiate mu receptor agonist that is widely used to substitute for illicit
opiates in the management of opiate dependence. It helps prevent opiate users from injecting and sharing
needles which are vehicles for the spread of HIV and other blood borne viruses. This study has the objective of
determining the utility of daily methadone dose to predict retention rates and re-injecting behaviour among
opiate dependents.
Methods: Subjects comprised opiate dependent individuals who met study criteria. They took methadone based
on the Malaysian guidelines and were monitored according to the study protocols. At six months, data was
collected for analyses. The sensitivity and specificity daily methadone doses to predict retention rates and re-
injecting behaviour were evaluated.
Results: Sixty-four patients volunteered to participate but only 35 (54.69%) remained active and 29 (45.31%) were
inactive at 6 months of treatment. Higher doses were significantly correlated with retention rate (p < 0.0001) and
re-injecting behaviour (p < 0.001). Of those retained, 80.0% were on 80 mg or more methadone per day doses
with 20.0% on receiving 40 mg -79 mg.
Conclusions: We concluded that a daily dose of at least 40 mg was required to retain patients in treatment and
to prevent re-injecting behaviour. A dose of at least 80 mg per day was associated with best results.

Background it is opiate drug use. Malaysia has had to grapple with

Opioid dependence and injecting drug use is a serious drug use problems for as long as it can be remembered.
world-wide problem. As the global epidemic of heroin Despite the avowed objective of becoming “drug-free”
use continues, it adds an increasing burden, driving the by 2015, the country is still struggling to rid itself of the
AIDS epidemic in Malaysia and other parts of Asia, with menace. In 1986, HIV landed in Malaysia and soon it
consequent additional health, economics and social pro- got into the drug user population in the country and
blems. The primary modes of transmission of HIV injecting opiate use is now feeding the Malaysian epi-
remain to be unprotected penetrative sex and injection- demic [1]. Thus, of the 80,938 cumulative number of
drug use although other modes also contribute. Direct HIV infection in the country at the end of 2007, 58,135
blood contact as in the sharing of drug-injection equip- were injecting drug users [2]. The management of opiate
ment, is a particularly efficient means of transmitting dependence thus presents a great challenge.
the virus. In parts of South East Asia and in Malaysia, Methadone is a μ-opiate receptor agonist developed by
the epidemic is driven by injection-drug use. In Malaysia German scientists in the late 1930s. It was approved by
the U.S Food and Drug Administration (FDA) in 1947
* Correspondence: drnasirmohamadkb@[Link]
as a painkiller, and by 1950 oral methadone also was
† Contributed equally used to treat the painful symptoms of persons with-
1
Pharmacogenetic Research Group, Institute for Research in Molecular drawing from heroin [1,3,4]. In 1964, Dole’s team dis-
Medicine (INFORMM), Health Campus, Universiti Sains Malaysia, 16150
Kubang Kerian, Kelantan, Malaysia
covered that continous daily doses of oral methadone
Full list of author information is available at the end of the article were beneficial, allowing otherwise debilitated opioid
© 2010 Mohamad et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License ([Link] which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Mohamad et al. Harm Reduction Journal 2010, 7:30 Page 2 of 8
[Link]

addicts to function more normally [5-11]. An adequate relatively low daily dose [20]. Malaysia is no exception.
maintenance dose of methadone does not make the Indeed in private practice in Malaysia, the average dose
patient feel “high’ or drowsy, so the patient can gener- is only 10-20 mg methadone per day, and only 5% of
ally carry on a normal life. If used properly, methadone patients receive doses greater 80 mg/day [21]. Even in
is generally safe and non-toxic with minimal side effect the government sector where methadone is provided
[5-11]. free, average daily dose is below 40 mg [22]. The reason
With the advent of HIV/AIDS in the 80’s it slowly for this is probably not related to the variable pharma-
assumed a central role in the management of opiate cology of methadone but rather because many physi-
dependence where it has probably revolutionized the cians, have at the back of their mind, a belief that “zero
approach with the adoption of maintenance therapy. drug is best”. Some physicians also fear the severe
Methadone maintenance reduces injection drug use [12] adverse drug response and fatal cardiac problems with
and is effective in reducing illicit heroin use, HIV risk methadone [23,24]. Inadequate doses and premature ter-
behaviors, HIV and other harms associated with illicit mination are the greatest threats to a successful MMT
opiate/heroin use [12-14]. Methadone prevents absti- program in Malaysia. Malaysian doctors tend to use low
nence syndrome, reduces narcotic cravings and block doses despite the fact that the traditional dosing with
the euphoric effects of illicit opiate use while reducing lower doses are expected to be ineffective [25]. Malay-
the risk for HIV and other BBV transmission. The abil- sian doctors may outwardly say that they use lower
ity of methadone to stabilize opiate dependent indivi- methadone doses because of their fear for ethnic differ-
duals provides a platform for addressing the other ence that would put their patients at higher risks for
biological and social dimensions of opiate dependence. toxicity if they were to use doses as high as those
Many countries have adopted MMT and MMT is now recommended by the Western literature. What they
the most widely used and effective pharmacologic treat- may not want to admit is the fact that, inwardly, they
ment for opiate dependence [15,16]. Apart from bring- have fears with methadone (and all opiates actually!) just
ing health benefits, MMT also reduces illicit opiate use, for the simple reason that methadone is an opiate, just
improves personal and social functioning and reduces like the dreaded heroin and morphine!. Indeed Malay-
drug related crimes [1]. sian doctors are not alone in this. Many doctors every-
Harm reduction came to Malaysia via the Harm Reduc- where share the same view. Thus, despite ample
tion Working Group at the Malaysia AIDS Council. evidence for the need to maintain patients at a daily
Their efforts culminated in the Government approving dose of 80 mg to 100 mg, most patients are maintained
harm reduction in 2003 but it was not until 2005-2006 on much less, and many are encouraged early termina-
that Methadone Maintenance Therapy (MMT) was intro- tion. It is probably understandable that the lay public
duced to be followed by the Needle and Syringe may not understand the scientific basis for MMT and
Exchange Program (NSEP) and the provision of condoms could be disparaging and become critical of it. It is how-
[17] apart from the provision of the usual educational ever less clear why many physicians and other health
material. As it is with many diseases, MMT is not a cure- care providers have the same views. Even those directly
all. It is for this that NSEP is offered. In the private sector involved with MMT programs frequently fail to adhere
in Malaysia, patients may also obtain alternative therapy to the basic principles of MMT. Most have actually
with buprinorphine. received clear information on the pharmacologic princi-
Methadone maintenance therapy (MMT) is generally ples underlying MMT and their claim that they want to
considered as corrective therapy, rather than as a “cure” prescribe as few medications as possible sound hollow,
for opioid addiction, and it had no or only limited effi- as they frequently easily prescribe other mood altering
cacy in treating dependence on other substances of drugs, such as the benzodiazepines that are often pre-
abuse [1]. At appropriate doses it not hinder a patient’s scribed with abandon and can produce psychological
intellectual capacities or abilities to perform tasks [18] and physiologic dependency. Even if they claim they fear
and it can correct the compulsive use of heroin and adverse effects, the adverse, physiologic effects of MMT
other opiates by addicts [6]. are minimal and methadone is probably associated with
Many factors contribute to the success of MMT but the least side effects of any drug in a physician’s phar-
studies have shown that adequate methadone dosing is macologic armamentarium, when used appropriately.
critical [19]. This is because the dose used must be able The real reason is probably more to do with the general
to prevent withdrawal, to block craving and perhaps to “opiophobias” as it is known that some doctors even
also block the effect of additional heroin to discourage hesitate to use opiates even when indications are clear.
patients from reverting to heroin. For therapeutic suc- Efforts should therefore be made urgently to reeducate
cess, adequate methadone dosing is critical. World-wide, these doctors. In their hands is the future of the nation.
the dose of methadone varies, with a tendency for a Their failure to prescribe adequate methadone doses
Mohamad et al. Harm Reduction Journal 2010, 7:30 Page 3 of 8
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will lead to therapeutic failure for MMT. This has dire opiate dependent individuals who met the inclusion and
consequences. exclusion criteria (Table 1) of the national MMT pro-
Our physicians justify the lower methadone doses gram. They gave a written consent prior to the enroll-
used on account of the smaller body sizes of their [26] ment. They were initiated on a methadone dose based on
and the possibility of reduced drug metabolisms [27]. the guidelines of the Malaysian Ministry of Health. The
However, drug metabolism and drug doses do not administration of methadone was directly observed by
depend on the body weight alone. It is more likely to be the prescribing physician. Patients were monitored
related to the expression level and catalytic activity of according our study protocols and the guidelines to
the putative drug metabolising enzymes (DME) in the monitor opiate usage and injecting behavior. At six
individual patients [28]. With methadone, metabolism is months, data was collected for analyses.
complex, mediated by several polymorphic DMEs as
reflected by the large variability observed with metha-
Statistical Methods
done disposition and half lives [29-31]. DME poly-
At the end of six months, patients’ data were collated.
morphisms have large geographic and ethnic variations
Patients were divided into 3 groups according to the
[32]. With CYP2B6 and CYP3A4, two enzymes that
daily dose level that they received, “low dose” (0-39 mg),
have been implicated in methadone metabolism, the
“intermediate dose” (40-79 mg) and “high dose” (80 mg
ethnic groups in Malaysia show polymorphism with
or more) [19]. Summary statistics were calculated.
types and frequencies that differed from each other and
Differences between groups were tested for signifi-
from ethnic groups in other geographic location [33].
cance using the chi-square test and p value of less than
Furthermore, the frequencies for mutations at CYP3A4
0.05 was taken as signifying statistical significance.
locus were found to be higher among Malay opiate
Additionally, sensitivity, specificity, positive predictive
dependent individuals compared to non-opiate depen-
value (PPV) and negative predictive value (NPV) were
dent Malays. CYP3A4 is an enzyme whose activity is
also calculated using the following formula and defini-
also altered by environmental factors like char-broiled
tion. This was done with the view of using daily dose
food and grape fruits [34]. All these would probably
groups to predict successful methadone therapy, i.e.,
have more impact on methadone dose requirements in
knowing the daily dose, how sure we are that MMT will
Malaysia than would body weights. However, given the
give good outcomes in the affected patients. For the pur-
body of the literature that support the need for adequate
pose of data analysis “inadequate dose” methadone group
dose, the low doses used can lead to reduced effective-
and “adequate dose” methadone groups were classified.
ness and thus negating the objective of the programmed.
“inadequate dose” group is defined as daily methadone
Remaining in treatment for an adequate period of
doses of less 80 mg and “adequate dose” group is defined
time is critical for treatment effectiveness. The appropri-
as daily methadone dose of more than 80 mg.
ate duration for an individual depends on their pro-
blems and needs, but research indicates that for most Sensitivity =
Number of true positive
× 100%
drug users, the threshold of significant improvement is Number of true positive + Number of false negative

reached only after about three months in treatment,

with further gains as treatment is continued. Because Number of true negative
Specificity = × 100%
people often leave treatment prematurely, and prema- Number of true negative + Number of false positive
ture departure is associated with high rates of relapse to
drug use, programmes need strategies to engage and Number of true positive
PPV = × 100%
keep patients in treatment. Number of true positive + Number of false positive
This paper reports retention rates and injecting beha-
viour in pilot patients given different doses of daily
Number of true negative
methadone in MMT programme, two parameters that NPV = × 100%
Number of true negative + Number of false negative
are very important for MMT in preventing the spread
of blood borne viruses. This study was performed to For retention rate, the true positive is defined as those
provide a platform for further studies on the pharmaco- patients on “adequate dose” who remain active on treat-
logic optimisation of methadone dose to attain its maxi- ment, true negative is defined as those patients on
mum benefits. “inadequate dose” and are defaulter to treatment, false
positive is defined as those patients on “inadequate
Methods dose” but remain active and false negative is defined as
Patients those patients on adequate dose but defaulted treatment.
The study was approved by the ethical committee at the For re-injecting behavior, the true positive is defined as
University of Malaya Medical Centre. Patients comprised those patients on “adequate dose” and not re-injecting,
Mohamad et al. Harm Reduction Journal 2010, 7:30 Page 4 of 8
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Table 1 The criteria of enrollment as recommended by Ministry of Health, Malaysia

Criteria Inclusion Exclusion
1. Opiate dependence by DSM IV criteria 1. Defaulter treatment for more than 3 days.
2. Age 18 years and above 2. Behavior judged by treating physician to be destructive to MMT clinic.
3. Willing to comply with the daily Direct Observation
Therapy Supervision (DOTS) and dosing.

true negative is defined as those patients on “inadequate Retention rate for the 40 - 79 mg per day dose group
dose” and has re-injecting behavior, false positive is was 20%. As shown in Table 3 and 4, the differences
defined as those patients on “inadequate dose” but show between the dose groups in terms of retention rates
no re-injecting behavior and false negative is defined as reached and re-injecting behavior statistical significance
those patients on “adequate dose” but exhibit re-injecting (p = 0.001).
behavior. All statistics were performed using SPSS (SPSS In terms of using methadone daily doses greater than
Inc, Ill, v 13) on an IBM-compatible computer. 80 mg as a predictor of a successful outcome for MMT
(as measured by retention rates and re-injection beha-
Results vior), we found that the positive predictive value of
Sixty-four patients were enrolled for this pilot study. All doses greater than 80 mg a day to predict retention was
were Malay males. The youngest was 20 years old and 80% and its negative predictive value was 93%. This
the oldest 56. All have had a long history of illicit drug means that, in terms of predicting retention, a daily
use exceeding 2 years. The youngest age at which they dose exceeding 80 mg will have a probability of 0.8 in
first took illicit drugs was 12 years. Their doses were accurately predicting that the patient will be retained in
titrated appropriately as tolerated and the final dose treatment. In terms of predicting failure to retain, it has
averaged 57.2 mg (SD ± 22.7) with a range from 20 to a probability of 0.93 in making an accurate prediction.
160 mg per day and a median of 50 mg. Table 2 details A similar probability was also calculated with regards
the characteristics of the study patients. re-injecting behavior but in terms of predicting non-
Overall retention rate at 6-month was 54.69% with 29 re-injecting, the probability of accurate prediction is
patients lost to follow up. Of the “retained” patients, only 0.73.
80% were receiving doses of 80 mg or more per day.
None was found in the 0 - 39 mg per day dose group. Discussion
Over time, many important discoveries have revolutio-
Table 2 Demography of study patients nized the practice of medicine. The discovery of penicil-
lin and other antibiotics for instance, have changed the
Details N %
ways infectious diseases are treated and the discovery of
Gender:
X-rays has introduced new ways for diagnostics. Metha-
-Male 64 100
done could have occupied a similar position but for the
-Female 0
stigma and discrimination that drug use disorder and
Age:
opiate use suffer from.
-Youngest 20
The 21 st century saw Malaysia leading the pact of
-Eldest 56
countries with a most rapidly rising HIV epidemic. After
-Mean: 33
tireless efforts by individuals and organizations, MMT
Age at 1st time illicit drug use
was finally instituted in the country. The program is
-As young as 12 year-old
now implemented at public and private health facilities
-As old as 32 year-old
and other facilities involved with drug use communities.
-Mean 20 year-old
The primary goal is to blunt the rapid rise in HIV infec-
Duration of Opiate Addiction:
tions although the public mainly see it as a treatment
-Minimum 2 years
for drug addiction. This paper reports a finding from a
-Maximum 38 years
pilot project on MMT in a small cohort of injecting
-Mean 13 years
drug users in SAHABAT and Klinik Dr Khafiz. It is
HIV infection status
intended to provide a basis for a more comprehensive
-Positive 23 36
research to understand factors that can contribute to
-Negative 37 58
successes with MMT as, among heroin drug users,
-Unknown 4 8
MMT has demonstrated effectiveness in reducing HIV
Mohamad et al. Harm Reduction Journal 2010, 7:30 Page 5 of 8
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Table 3 Retention status of patients in MMT programme at 6 months follow-up

Retention Group of Methadone Doses Total p-value Sensitivity Specificity Positive predictive value Negative predictive value
Status at 6 (PPV) (NPV)
months
80 mg & 80 mg &
below above
Active n 7 28 35
% 20 80 100
Defaulter n 27 2 29 0.001 80.00% 93.10% 93.30% 79.40%
% 93 7 100
Total n 34 30 64
% 53 47 100

risk behaviors and HIV infection [12-14]. MMT pro- Drug use disorder is a chronic relapsing disease. Our
grams in Malaysia are implemented in government hos- study revealed that no age group is spared. Our young-
pitals as well as in private practice. est patient was 20 years-old. They began their drug
SAHABAT is a non-governmental organisation work- habit as early as when they were 12 years. The oldest
ing for and with drug use communities in Kelantan. patient was 56 years and the oldest age a patient started
MMT was introduced in SAHABAT in 2008. SAHA- with the habit was 32 years. The duration of illness
BAT is the first centre in Malaysia to have both the among our patients ranged from two years to 38 years
MMT program and NSEP running under one roof. and averaged 13 years. These have implications. For
SAHABAT also boasts as the only NGO-run centre that one, preventive measures for drug use disorder must
was allowed to prescribe methadone. The other centre begin early and should be continued through all ages.
included in this study was Klinik Dr Khafiz, a general Patients afflicted with the disease should also have long
practice clinic near Kuala Lumpur. It was included to follow ups as they evidently continue with their habits
provide an insight of MMT practice in the community. right through their golden years. The longer they con-
In this study, all the patients enrolled were males in tinue on the habit, the greater is the chance for them to
the productive age group. This underscores the impor- contract diseases like HIV, if they have not yet been
tance of proper management of opiate addiction because infected. Being young and otherwise healthy, young
of its potential influence on population growth, demo- addicts may find themselves constrained in various
graphy as well as productivity of the nation as young activities and this may lead them to many other
males play a significant role in providing Malaysia’s unhealthy practices.
work force. Of note was a high prevalence of HIV posi- Drug users do not live in isolation. Apart from trans-
tivity. In most countries that practice harm reduction mission through the sharing of injection equipments,
among injecting drug users, the incidence of HIV posi- having the HIV reservoir, drug users can also transmit
tivity is generally 1-2% [35]. The high prevalence seen in the disease to their sexual partners, through penetrative
our Malaysian cohort suggests the need for urgent effec- sex. Thus, what started in Malaysia as a concentrated epi-
tive measure to control. This is now done in Malaysia demic among drug users is now showing evidence for a
with MMT and NSEP. more generalized epidemic through sexual transmission.

Table 4 Re-injecting behaviour of patients in MMT programme at 6 months follow-up

Re- Group of Methadone Doses Total p-value Sensitivity Specificity Positive predictive value Negative predictive value
injecting (PPV) (NPV)
behaviour
at 6
month
80 mg & 80 mg &
below more
Yes n 24 9 33 0.001 71.00% 73.00% 71.00% 73.00%
% 73 27 100
No n 9 22 31
% 29 71 100
Total n 33 31 64
% 52 48 100
Mohamad et al. Harm Reduction Journal 2010, 7:30 Page 6 of 8
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In the beginning, less than one percent of HIV victims methadone doses because of fear for ethnic difference
were females. Now it stands at about 20% and this clearly that would put patients at risks for toxicity. They will
demonstrates the generalization of the HIV epidemic in not admit their fears with methadone (and all opiates
Malaysia. Most of the afflicted females are also wives and actually!) just for the simple reason that methadone is
spouses of drug users who are themselves HIV positive an opiate, just like heroin and morphine!. Malaysian
and not sex workers as many would have expected. doctors are not alone in this. Despite evidence for the
There is however evidence for a growing epidemic need for a daily dose of 80 mg to 100 mg, most patients
among sex workers and this again has the potential to are maintained on much less. It is probably understand-
generalize into the community. able that the lay public may not understand the scienti-
A most important characteristic of a good MMT pro- fic basis for MMT and could be disparaging and
gram is high retention rate [36]. Our overall retention become critical of it. It is however less clear why many
rate at 6 months was low. Coupled with the relatively physicians and other health care providers have the
small percentage of opiate-dependent individuals having same views. Most have actually received clear informa-
access to MMT in Malaysia, this may threaten the suc- tion on the principles underlying MMT. They may also
cess of MMT as a tool to reduce HIV spread in Malaysia. claim that they want to prescribe as few medications as
The low retention rate we saw was probably due to the possible but this sounds hollow. Many frequently easily
low daily maintenance dose of methadone our patients prescribe other mood altering drugs, such as the benzo-
got. Our daily doses averaged 57 mg. Its median was diazepines that can also produce psychologic and phy-
lower at 50 mg. Our results revealed that best retention siologic dependency. Even if they claim they fear
rates were obtained among patients treated with 80 mg adverse effects, the adverse, physiologic effects of MMT
or more methadone per day. In parallel, our patients trea- are minimal and methadone is probably associated with
ted with 80 mg or more methadone per day showed the the least side effects of any drug in a physician’s phar-
least tendency for re-injecting. It is therefore interesting macologic armamentarium, when used appropriately.
to note that, despite claims by many physicians that rela- Illicit use of benzodiazepines, even among MMT
tively lower doses of methadone would be sufficient for patients, are now threatening to derail the MMT pro-
our Malaysian patients, our results showed otherwise. gram as many continue to inject benzodiazepines
Our findings were also in parallel with studies that although they may have discontinued injecting opiates.
showed a sufficiently high dose was required for There is probably a general “opiophobias”. It is known
improved outcomes [37]. High doses suppress illicit her- that some doctors even hesitate to use opiates even
oin use and improve retention and outcomes [38,39]. when indications are clear. Efforts should therefore be
Dole’s original research discovered that 80 to 120 milli- made urgently to reeducate these doctors. In their
grams of methadone per day, on average, was an effective hands is the future of the nation. Their failure to pre-
dose. Dozens of studies since then have demonstrated scribe adequate methadone doses will lead to therapeu-
that dosing in that range resulted in superior treatment tic failure for MMT and this has dire consequences.
outcomes, such as better retention of patients in treat- Our physicians justify the lower methadone doses used
ment and less illicit drug use [9,11,39]. Patients main- on account of the smaller body sizes of their [26] and the
tained on inadequately low doses are much more likely possibility of reduced drug metabolisms [27]. However,
to use illicit opioids and respond poorly to therapy [18]. drug metabolism and drug doses do not depend on the
A study by Strain et al [40] also concluded that patients body weight alone. It is more likely to be related to the
receiving 80 mg or more methadone per day had signifi- expression level and catalytic activity of the putative drug
cantly greater decreases in illicit opiod use. Another metabolising enzymes (DME) in the individual patients
study concluded that a sufficiently high dose of substitu- [28]. With methadone, metabolism is complex, mediated
tion therapy was required for improved outcome [37] by several polymorphic DMEs as reflected by the large
and many other independent studies also showed that variability observed with methadone disposition and half
high doses of methadone were significantly more effec- lives [29-31]. DME polymorphisms have large geographic
tive in suppressing illicit heroin use and in retaining and ethnic variations [32]. With CYP2B6 and CYP3A4,
patients in the treatment [38,41,42]. two enzymes that have been implicated in methadone
Inadequate doses and premature termination will metabolism, the ethnic groups in Malaysia show poly-
probably be the greatest threats to a successful MMT morphism with types and frequencies that differed from
program in Malaysia. Malaysian doctors tend to use low each other and from ethnic groups in other geographic
doses despite the fact that the traditional dosing with location [33]. Furthermore, the frequencies for mutations
lower doses are expected to be ineffective [43]. Many at CYP3A4 locus were found to be higher among Malay
also actively encourage their patients to terminate MMT opiate dependent individuals compared to non-opiate
early. They may outwardly say that they use lower dependent Malays. CYP3A4 is an enzyme whose activity
Mohamad et al. Harm Reduction Journal 2010, 7:30 Page 7 of 8
[Link]

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doi:10.1186/1477-7517-7-30
Cite this article as: Mohamad et al.: Better retention of Malaysian opiate
dependents treated with high dose methadone in methadone
maintenance therapy. Harm Reduction Journal 2010 7:30.

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