Substance Use & Misuse

ISSN: 1082-6084 (Print) 1532-2491 (Online) Journal homepage: http://www.tandfonline.com/loi/isum20

Can Tramadol be Used for Maintenance Treatment

of Opioid Dependence?

Siddharth Sarkar, Rakesh Lal, Mohit Varshney, Saurabh Kumar & Yatan Pal
Singh Balhara

To cite this article: Siddharth Sarkar, Rakesh Lal, Mohit Varshney, Saurabh Kumar & Yatan Pal
Singh Balhara (2018): Can Tramadol be Used for Maintenance Treatment of Opioid Dependence?,
Substance Use & Misuse, DOI: 10.1080/10826084.2018.1521427

To link to this article: https://doi.org/10.1080/10826084.2018.1521427

Published online: 05 Nov 2018.

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SUBSTANCE USE & MISUSE
https://doi.org/10.1080/10826084.2018.1521427

Can Tramadol be Used for Maintenance Treatment of Opioid Dependence?

Siddharth Sarkar , Rakesh Lal, Mohit Varshney, Saurabh Kumar, and Yatan Pal Singh Balhara
National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India

ABSTRACT KEYWORDS
Background: Certain limitations of the existing opioid substitution therapies necessitate Harm reduction;
exploration of other options for maintenance of patients with opioid dependence. This maintenance treatment;
study aimed to present the experience of use of tramadol for long-term treatment of opioid dependence;
opium; tramadol
patients with opioid dependence. Methods: This was a cross-sectional interview-based
observational study conducted in Uttar Pradesh state in India. Patients with opioid
dependence who received oral tramadol treatment for a period of more than 6 months
were recruited. Outcome was assessed in terms of self-reported abstinence on tramadol.
Results: A total of 102 participants were recruited in the study, with a mean age of
41.3 years. All the participants were males. Abstinence to extraneous opioids was reported
by 58.8% of the sample, and the median dose of tramadol at which abstinence was
achieved was 350 mg/d. Those who reported to be taking natural opioids (raw opium or
poppy husk) at the time of seeking treatment had higher rates of achieving abstinence.
Conclusions: Tramadol may be a possible option for the maintenance treatment among
some opioid-dependent individuals. Further studies are required to establish its efficacy
vis-
a-vis other medications used in opioid substitution treatment.

Introduction Many patients move between these two treatments

Opioids continue to be the main problem drug
worldwide, accounting for some 60% of treatment
demand in Asia and in Europe (UNODC, 2015).
More than half of the world’s opioid using population
lives in Asia, with the highest levels of abuse
occurring along the main drug trafficking routes out
of Afghanistan (United Nations, 2015). Opioid abuse
continues to rise in Asia, mainly among countries
close to Afghanistan including India, Bangladesh,
Nepal, Bhutan Pakistan, the Central Asian countries
and the Russian Federation (Ghotbi & Tsukatani,
2007). Thus, opioid dependence is likely to be a
major clinical and public health challenge in the
region, necessitating expansion of treatment services
and therapeutic options.
One of the most efficacious and cost-effective
treatment for long-term management of opioid
dependence is opioid substitution therapy (OST).
Methadone and buprenorphine are the commonly
used OST medications which have been in use for
decades now (Darke & Farrell, 2016; Dennis et al.,
2014; Kermode, Crofts, Kumar, & Dorabjee, 2011;
Lawrinson et al., 2008; Zippel-Schultz et al., 2016).
over the course of time, depending on their needs in
terms of dispensing (Gutwinski, Bald, Gallinat, Heinz,
& Bermpohl, 2014; Ling, Rawson, & Compton, 1994;
Prakash &Balhara, 2016; Threlkeld, Parran, Adelman,
Grey, & Yu, 2006). Despite the scale-up of OST
services in certain areas like India and South Asia, the
overall coverage of OST remains low; and various
barriers exist between service providers and recipients
(Rao, Agrawal, Kishore, & Ambekar, 2013). One of
these barriers reported by the recipients is the
dispensing pattern and the need to come frequently
to the centers for obtaining the mediation (Oliva,
Maisel, Gordon, & Harris, 2011; Richardson, Wood,
Montaner, & Kerr, 2012; St€ over, 2011). Restrictive
policies in supply and clinical use of these medications
deter away physicians from recommending OST as an
option. Moreover, lack of therapeutic options has also
been suggested as a structural barrier for treatment
(Sharma & Chatterjee, 2012).
Hence, there is a need to explore other options
for long-term management of opioid dependence.
Previously, several options have been tried for opioid
substitution. These include medications like slow

CONTACT Siddharth Sarkar sidsarkar22@gmail.com Department of Psychiatry and NDDTC, All India Institute of Medical Sciences, Room No 4096,
Teaching Block, New Delhi 110029, India.
ß 2018 Taylor & Francis Group, LLC
2 S. SARKAR ET AL.
release oral morphine and codeine, though the litera-
ture is limited (Ferri, Minozzi, Amato, Bo, & Davoli,
2013; Krausz, Verthein, Degkwitz, Haasen, & Raschke,
1998). Tramadol has been found to have good efficacy
in the treatment of opioid withdrawals, particularly of
mild to moderate severity (Lofwall et al., 2013;
Lofwall, Walsh, Bigelow, & Strain, 2007; Mandal &
Prakash, 2015). Anecdotal evidence exists suggesting
that tramadol can be used for the long-term treatment
of opioid dependence in selected individuals (Gyawali
& Sarkar, 2016; Tewari & Sarkar, 2017). Low abuse
potential and safety in moderate doses makes it a
possible candidate for long-term treatment of opioid
dependence (Babalonis, Lofwall, Nuzzo, Siegel, &
Walsh, 2013; Boostani & Derakhshan, 2012; Cicero
et al., 2005 Threlkeld et al., 2006). We have previously
published a retrospective chart review study of
patients with opioid dependence who had been
maintained on tramadol (Sarkar, Lal, Varshney, &
Balhara, 2017). We present here our prospective inter-
view-based study of patients with opioid dependence
who received treatment with tramadol for substantial
periods of time.
Methods
Study setting and participants
This descriptive observational self-report based study
was conducted at the National Drug Dependence
Treatment Centre (NDDTC); a tertiary care center for
the treatment of substance use disorders in northern
India in Uttar Pradesh state. The center is a public-
funded institution and receives both referred and
non-referred patients. The center receives a substantial
proportion of patients with opioid dependence who
have been taking either heroin natural opioids or
prescription opioids. Natural opioids include raw
opium or poppy husk, and these have been in use in
parts of South Asia for a long time (Ganguly, Sharma,
& Krishnamachari, 2006). Natural opioid users
constitute about one-fifth of the treatment-seeking
opioid-dependent individuals in the region (Basu
et al., 2012). A recent population survey suggests
that natural opioids are probably the second most
common type of opioids being abused in the region
(Ambekar et al., 2015).
The patients seeking treatment at the NDDTC are
diagnosed using ICD 10 classification system by
trained psychiatrists. Treatment is started after intake
interview based upon clinical needs. The patients
with opioid dependence are typically prescribed
buprenorphine for opioid agonist maintenance or for
withdrawal management. However, considering
the risk of diversion, patients generally receive daily
supervised dosing from the center in the initial period.
A subset of patients who are unable to take supervised
buprenorphine are offered oral tramadol for managing
withdrawals on out-patient basis, with the aim of
tapering down the dose (i.e. detoxifying) over the
course of a few weeks. Tramadol is prescribed gener-
ally for a period of 2–3 weeks and is dispensed from
the center. Some of the patients who are prescribed
tramadol seem to experience reduction of withdrawal
symptoms. Yet, many find it difficult to taper off the
doses of tramadol over the course of follow-up and
hence, continue to take it for considerable periods of
time in order to abstain from illicit opioid use. This
study aimed to evaluate such patients who received
tramadol without completely tapering it off over a
course of 6 months. The inclusion criteria were:
patients with a diagnosis of opioid dependence
according to ICD 10 criteria (World Health
Organization, 1992), aged 18 and above, and having
received tramadol over a period of more than
6 months (verified from the prescriptions). Those who
refused informed consent or those who had significant
withdrawal symptoms were excluded from the study.
Study procedure
This was a cross-sectional observational interview-
based study. The participants who fulfilled the inclu-
sion and exclusion criteria were evaluated with the
help of a semi-structured questionnaire by one of the
investigators. The questionnaire included demographic
details, substance use details, information related to
tramadol use, any adverse events, and their preferen-
ces toward tramadol. The duration of use of tramadol
was also recorded. The outcomes of the patients in
terms of attainment of cessation of other opioid use
were also ascertained. Abstinence status was assessed
with self-report of the patient and corroboration with
family members when available. Abstinence was oper-
ationalized as cessation of extraneous/illicit opioid use
for a period of at least 1 month. Follow-up adherence
was computed as a percentage by dividing the number
of times patients actually turned up for follow-up or
prescription refill by the number of times they were
asked to during the course of treatment. Additionally,
the patients were asked about diversion of prescribed
tramadol and the maximal dose used. The question-
naire was clinician-administered and was developed
for this study. Data collection lasted from January
2017 to May 2017, and the target sample size was
 SUBSTANCE USE & MISUSE 3

about one hundred patients based on exploratory sample was 41.3 years (range of 19–70 years). A
nature of the study. The study has institutional ethics majority of the participants were married, were
committee approval (IEC/521/10/2016). educated up to the 10th grade, lived in an extended
or a joint family, and were from rural background.
The median duration of opioid use was 12 years with
Statistical analysis
a range from 1 to 45 years. A substantial proportion
The analysis was primarily descriptive in nature and of participants in the study reported to be taking
was conducted using SPSS version 21 (IBM Corp, natural opioids (poppy husk or raw opium) prior to
Armonk, NY). Mean, standard deviation, median, seeking treatment at the center; followed by heroin
range, frequency, and percentages were used to users. The most common diagnosis related to another
represent the data. Inferential statistics was used to substance of user pertained to tobacco, followed by
assess relationship between the variables of interest. cannabis, alcohol, and benzodiazepines.
Student’s t test, Mann–Whitney U test and v2 test The reason of initiation of tramadol was reported
were used as applicable. A p value of less than .05 was to be logistic problems in coming daily for buprenor-
considered significant for the tests of significance. phine dispensing in all the patients. The tramadol
Missing value imputation was not performed for treatment-related characteristics of the sample are
this study. shown in Table 2. The table also shows the same
characteristics of patients who were users of natural
opioids. The median dose of tramadol initiation and
Results the most common dose of prescribed tramadol was
A total of 102 participants were enrolled in the study. 300 mg/d. The median maximum dose during the
The demographic and clinical characteristics of the course of treatment was reported to be 350 mg/d. The
sample are shown in Table 1. All the participants in median duration of tramadol treatment at the center
the study comprised of males. The mean age of the was 8 months. The median follow-up adherence was
80%. About 60% of the patients admitted to have
Table 1. Demographic characteristics of the sample. taken excess doses of tramadol than prescribed.
Mean (SD) or Sixty out of a total of 102 participants (58.8% of
Socio-demographic variable frequency (percentage)
the sample) achieved abstinence to extraneous opioids
Age in years 41.3 (14.2)
Gender at least for a period of one month. Among the rest
Male 102 (100%) 42 participants, 39 reported reduction in the use of
Marital status
Currently married 87 (85.3%)
extraneous opioids. Taken together, 99 patients (about
Currently not married 15 (14.7%) 97.1% of the sample) were deemed to have some
Educational status
Not formally educated 28 (27.5%)
benefit with oral tramadol. Further exploratory
Educated up to 10th grade 67 (65.6%) analysis was done to find relationship of becoming
Educated above 10th grade 7 (6.9%) abstinent with other clinical variables. It was seen that
Living arrangement
Alone 4 (3.9%) the rates of achieving abstinence were higher among
Nuclear family 31 (30.4%) users of natural opioids compared to others (81.6%
Extended/joint family 67 (65.7%)
Religion versus 37.7%, v2 ¼ 20.255, d.f. ¼ 1, p<.001). Also,
Hindu 59 (57.8%) older patients (mean age 45.1 versus 35.9 years,
Sikh 19 (18.6%)
Islam 24 (23.5%) t ¼ 3.385, p ¼ .001), those with long duration of opioid
Clinical parameters use (mean 17.8 versus 11.7 years, U ¼ 839.0, p ¼ .004)
Diagnosis with relation to opioid use
Dependence (ICD 10) 102 (100%) and those who had a better follow-up adherence
Duration of opioid use in years 12 (1–45) (mean 80.5% versus 60.0%, U ¼ 475.5, p < .001)
Type of opioids being used before
seeking treatment here seemed to have higher rates of achieving abstinence.
Natural opioids 49 (48.0%) The dose of tramadol being prescribed or the duration
Heroin 31 (30.4%)
Prescription 3 (2.9%) of treatment with tramadol did not have a relationship
Mixed 19 (18.6%) with the achievement of abstinence.
Other diagnoses (ICD 10)
Tobacco dependence 92 (90.2%)
Among the 60 participants who had achieved
Cannabis dependence 10 (9.8%) abstinence, 31 had relapsed to extraneous opioid use
Alcohol dependence 7 (6.9%) (a little over 50%). The type of opioids being used,
Benzodiazepine 5 (4.9%)
ICD10: International Classification of Diseases and Health Related
age of the participant, and dose of tramadol did not
Conditions, 10th Edition. have a relationship with the propensity of relapse.
4 S. SARKAR ET AL.

Table 2. Treatment-related characteristics of the sample.

Variable Entire sample (n ¼ 102) Natural opioid users (n ¼ 49)
Dose of tramadol at initiation 300 (200–400) 300 (200–400)
Maximum dose of tramadol prescribed 350 (200–450) 350 (250–450)
Most common dose of tramadol prescribed 300 (200–450) 300 (200–400)
Duration of tramadol treatment in months 8 (6–30) 9 (6–30)
Follow-up adherence in percent 80 (25–100) 81.5 (50–100)
Did the patient take excess doses than prescribed 60 (58.8%) 26 (53.1%)
Maximum doses of tramadol taken by patient 400 (200–1000) 400 (250–600)
Side effects experienced with maximum doses 9 (15.0%) 4 (8.2%)
Abstinence achieved on prescribed tramadol 60 (58.8%) 40 (81.6%)
Dose at which abstinence achieved 350 (250–400) 300 (250–400)
Duration of abstinence if abstinence achieved (months) 6 (1–18) 6 (1–18)
Reduction of illicit opioids if abstinence not achieved 39 (92.9%) 9 (100%)
Relapse to extraneous opioids after achieving abstinence 31 (51.7%) 22 (44.9%)
Reasons of relapse
Withdrawals 15 (48.4%) 12 (54.5%)
Peer pressure 5 (16.1%) 5 (22.7%)
Medication discontinuation 4 (12.9%) 1 (4.5%)
Craving 3 (9.7%) 2 (9.1%)
Others† 4 (12.9%) 2 (9.1%)
Adverse events with tramadol
Seizures 1 (1.0%) 0 (0%)
Increased use of other substances after tramadol initiation 3 (2.9%) 0 (0%)
Shown as frequency (percentage) or median (range), doses mentioned in mg/day.
†
Others included negative mood, pain, work pressure, and multiple factors for 1 patient each.

Table 3. Treatment-related characteristics of the sample.

Variable Entire sample (n ¼ 102) Natural opioid users (n ¼ 49)
Did the patient ever try buprenorphine 58 (56.9%) 20 (40.8%)
Preferred opioid among buprenorphine or tramadol for those who have used both
Buprenorphine 49 (84.5%) 15 (75%)
Tramadol 9 (15.5%) 5 (25%)
Procured tramadol from chemist 11 (10.8%) 5 (10.2%)
Procured tramadol from others (but not chemists) 20 (19.6%) 9 (18.4%)
Gave own supply of tramadol to others 9 (8.8%) 5 (10.2%)
Reasons of giving own supply as mentioned by patients†
To help other patients in need 4 (50.0%) 3 (75%)
To exchange for buprenorphine 2 (25.0%) 1 (25%)
To get money 1 (12.5%) –
To show effect to other substance users 1 (12.5%) –
Shown as frequency (percentage).
†
Information available from 8 to 4 patients.

However, longer duration of opioid use was associated
with increased chances of relapse (mean 20.9 versus
15.5 years, U ¼ 309, p ¼ .034) and longer duration of
tramadol use was associated with greater chances of
relapse (11.4 versus 8.2 months, U ¼ 267, p ¼ .006). As
depicted in Table 2, only one patient reported an
adverse event while using prescribed dose of tramadol
in the form of a seizure.
Some of the other treatment-related characteristics
of the sample are shown in Table 3. More than half
of the patients who were on tramadol had tried
buprenorphine, and an overwhelming majority of
them preferred buprenorphine to tramadol. Yet, they
were constrained for prescription of tramadol. A
minority also reported procuring tramadol from a
chemist and other sources. The median going rate of
procuring tramadol from others was Indian Rupees 5
per tablet, or 50 per strip (a strip of 10 tablets costing
roughly less than US$1). Less than a tenth of the
sample reported that they gave their own supply of
tramadol to others, primarily to “help” other patients
in need who could not procure tramadol.
Discussion
This study indicates towards some support that trama-
dol may have a place in the long-term management of
opioid dependence, apart from its use for manage-
ment of acute withdrawal. Recommendation for its
use for long-term management has been made based
upon the low abuse liability of this medication (Das,
Jain, Dhawan, & Kaur, 2016; Mandal & Prakash,
2015). Moreover, it fits in with three of the four basic
assumptions of harm-reduction approach: reduction
of harms, client needs’ first and low threshold services
(Marlatt, 1996).
The goals of pharmacotherapy in long-term
management include prevention or reduction of

withdrawal symptoms, prevention, or reduction of
drug craving, prevention of relapse to addictive drug
use, and restoration toward normalcy of physiological
function disrupted by drug abuse (Kreek, 1992; Salsitz
& Wiegand, 2016). The pharmacological treatment is
contextualized in the service delivery characteristics
including access to care for medical, behavioral, and
rehabilitation related issues. In this study, approxi-
mately 60% opioid-dependent individuals achieved
abstinence. The proportion increased to more than
80% in patients using natural opioids. Moreover, less
than ten percent relapsed to their primary opioid of
abuse due to craving; indicating significant reduction
in this parameter while on tramadol. Additionally, in
the natural opioid group, no patient increased other
substance of abuse while on treatment. This may sug-
gest restoration of physiological function disrupted by
use of natural opioids prior to initiation of tramadol.
In central and south Asia, natural opioids have
been abused for centuries (Kulsudjarit, 2004); and
constitute up to 16% of treatment seekers in India
(Balhara, Mishra, Sethi, & Ray, 2013). A pro-heroin
effect has been described, i.e. increased propensity of
using heroin with decreased availability of natural
opioids in traditionally opium using population
(Ganguly et al., 2006; Westermeyer, 1976). This con-
stitutes significant potential burden on the health-care
system, despite the lesser harms perceived for natural
opioids compared to other illicit drugs (Sarkar,
Balachander & Basu, 2014). Thus, natural opioids
probably represent a sub-group whose treatment
needs may be different from other opioids. Tramadol
seems to be a possible therapeutic option for mainten-
ance treatment in natural opioid users. It seems to
fulfill five out of eight requirements for choosing
long-term agents for pharmacotherapy; i.e. being an
agonist, pharmacological stability, dose-response, and
reduction in craving and salience (Darke & Farrell,
2016; Kreek, Borg, Ducat & Ray, 2010).
However, an equally essential requirement for long-
term agent is safety, in terms of toxicity, and cognitive
and psychiatric sequelae following administration. The
neurotoxicity of tramadol commonly manifests as gen-
eralized tonic-clonic seizures and has been reported to
be more common in individuals consuming alcohol
and other illicit drugs concomitantly (Boostani &
Derakhshan, 2012). Available literature reports a lower
risk of seizures and other side effects when taken
in moderate doses (up to 400 mg) (Boostani &
Derakhshan, 2012; Marquardt, Alsop& Albertson,
2005). Furthermore, tramadol as a suitable long-term
agent does not meet the criteria of having single daily
SUBSTANCE USE & MISUSE 5
administration and ability to block the effect of
exogenously taken opioids (Driessen, Reimann, &
Giertz, 1993). Another important aspect of using
tramadol for long-term is the propensity of diversion.
The diversion is quite linked to policies of the
treatment facility and the dispensing regimen. We do
probably need to acknowledge that diversion did
occur among the participants. However, patients
preferred buprenoprhine over tramadol when they
had access to both, suggesting that buprenorphine
should probably be more tightly regulated.
Relapse to illicit opioids occurred in a substantial
proportion of individuals who attained abstinence in
this study. High relapse rates have been found in
other naturalistic studies of buprenorphine or metha-
done based OST (Wittchen et al., 2008). Yet, efforts
are required, especially in the form of concerted care
including psychosocial rehabilitation, to reduce these
relapse rates. A unique feature of this sample was that
it comprised of males exclusively. This could be
attributed to a very low proportion of females
accessing treatment services in this part of the world,
as well as treatment-related barriers that may lead
to discontinuation of treatment of women who
eventually seek care (Lal, Deb & Kedia, 2015).
Overall, the results of our study suggest that when
used in moderate dosages (300–400 mg) tramadol
appears to be a good alternative in the medium and
long-term management of a sub-population of opioid-
dependent individuals. When looked from a harm-
reduction perspective in the sub-population, it appears
to be a viable alternative for resource-limited settings
and warrants further research. Also, the restrictions
on prescription and sale of tramadol are lesser than
that of buprenorphine and methadone, making it eas-
ier to procure and dispense in the clinical setting for
therapeutic purposes by a wider range of practitioners
(Chawla et al., 2013; Stoops et al., 2012).
The study, however, has its own limitations in
terms of an observational design and included
only those individuals who completed 6 months of
treatment with tramadol. This could have biased the
findings as it would omit results of patients where tra-
madol might not have produced desired results. Also,
the information about abstinence was based upon self-
report without corroboration with biological samples.
The amount of opioids being used at the time of
initiation of the treatment was not accounted for
(given the different forms of opioids being used),
though the amount being consumed might have
influenced the outcome. The study was conducted in
a single center in a specific geographical location and
6 S. SARKAR ET AL.
the sample comprised only of males. More import-
antly, the access to other opioid substitution treatment
might be different in other centers and health systems,
and hence the necessity of using tramadol as an
option would be perceived differently. Hence, general-
ization of the study should be made with caution.
To conclude, tramadol seems to be an option for
the maintenance treatment of opioid dependence.
Seemingly patients who have been using natural
opioids seem to do better on this medication as
compared to others. Further research is required to
strengthen the evidence for tramadol as a maintenance
agent for opioid-dependent individuals, possibly using
objective measure of drug use like urine screening,
and subsequently a double-blind randomized
controlled efficacy trial with active comparator. The
utility and acceptability of this medication in the opi-
oid-dependent individuals needs further exploration.
Also, the safety profile needs to be assessed through
long-term follow-up. Nevertheless cross-sectional and
cohort-based information from the patients who are
maintained on this medication may also provide
valuable insights about utility of this medication as a
maintenance agent. The collected evidence can
eventually guide policy decisions for implementing
judicious use of tramadol in resource-limited settings,
or in circumstances where regulatory frameworks
restrict the use of other opioid agonists.
Declaration of interest
The authors declare that they have no conflict of
interest. The authors alone are responsible for the
content and writing of the article.
ORCID
Siddharth Sarkar http://orcid.org/0000-0002-3827-1549
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