Year : 2018 | Volume
: 60 | Issue : 3 | Page : 265--270
Research on opioid substitution therapy in India: A brief, narrative review
Atul Ambekar, Ravindra Rao, Alok Agrawal, Preethy Kathiresan
National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India
Dr. Atul Ambekar
National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi - 110 029
Opioid dependence is a significant clinical and public health issue in India. Opioid substitution therapy (OST) is the most evidence-based treatment for opioid dependence. Although available in India for about three decades now, Indian research on this treatment modality has not been adequately reviewed so far. We conducted a narrative review of Indian research on OST. We conducted an online search for relevant literature in the peer-reviewed journals as well as the general online search for books and monographs. We present the findings of the review in the form of description of literature according to certain identified themes. Considering that methadone has became available in India, only recently, the Indian research on OST predominantly features buprenorphine as the agent. Effectiveness of OST among Indian opioid-dependent patients has been well established through prospective, experimental designs as well as through naturalistic studies using retrospective, chart-review approach. Naturalistic and observational postmarketing surveillance studies have demonstrated the safety of buprenorphine and methadone when used as OST. There are certain areas in which more research on OST will be beneficial for Indian clinicians as well as policy-makers. However, the quantum of evidence base that exists in India is more than adequate to justify the scale-up of this modality of treatment. A conducive policy environment for scaling-up OST is need of the hour.
|How to cite this article:|
Ambekar A, Rao R, Agrawal A, Kathiresan P. Research on opioid substitution therapy in India: A brief, narrative review.Indian J Psychiatry 2018;60:265-270
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Ambekar A, Rao R, Agrawal A, Kathiresan P. Research on opioid substitution therapy in India: A brief, narrative review. Indian J Psychiatry [serial online] 2018 [cited 2019 Oct 14 ];60:265-270
Available from: http://www.indianjpsychiatry.org/text.asp?2018/60/3/265/243388
India is situated between the two largest illicit opium-producing regions of the world – “Golden Crescent” and “Golden Triangle,” which makes it vulnerable for being both a destination and transit route for opioids. Besides, India itself is one of the largest legal producers of opium. Not surprisingly, India has had an established pattern of use of opioid group of drugs. Indeed, a sizable number of people in India use opioid drugs, suffer from opioid dependence and seek treatment for the same. In the first and the only national survey till date on drug use in India, the prevalence of opioid use was found to be 0.7% of the general population among whom, around 22.3% were found to be dependent on opioids. India has twice the global average prevalence of illicit opiate consumption. It is estimated that currently, India has about 4 million people who use opioids and around 1 million people who are opioid dependent. A recent study reported that around 232,000 people were opioid dependent in Punjab alone. Thus, there is undoubtedly a sizable burden of opioid dependence in many parts of India.
The most evidence-based treatment strategy for opioid dependence is agonist maintenance treatment or opioid substitution therapy (OST).,, However, in India, availability of this treatment at the required scale continues to be a challenge., There may be a belief in certain quarters that Indian experience with OST as well as research evidence on OST in India may be limited. Thus, in this narrative review, we present the Indian evidence base regarding need, availability, and effectiveness of OST in India. For this article, we have searched for the literature on OST in India in peer-reviewed indexed journals. We also conducted an online search for relevant publications which are not available as journal articles but as books and monographs. We primarily focused upon examining the availability of literature on various aspects of OST in India. Being a narrative review, this article does not claim to be an exhaustive search of all the available literature. Rather, we have covered studies on different areas of OST research, and we thus seek to establish that a considerable quantum of academic work exists in India, on OST. We also explore the research gaps and provide certain recommendations for the future research.
Effectiveness of Opioid Substitution Therapy
Attempts to establish the effectiveness of OST in India began in parallel with the clinical application of this treatment since early 1990s. Mohan and Ray reported the findings of a project on community-based treatment for heroin addiction using buprenorphine. A total of 108 male patients with heroin dependence received sublingual buprenorphine for a period of 6–11 months along with psychosocial interventions. At follow-up, about 70% had improved indicating no use or very little use of heroin. Another small study was carried out in Nagaland, in which 54 male opiate-dependent patients were provided buprenorphine and were followed up to 6 months. The retention rate was 81.5% at 24 weeks. A significant improvement was reported on follow-up assessment on various parameters including the scores on Addiction Severity Index as well as on frequency of drug use. Although these early studies did document the effectiveness of buprenorphine-based OST, they were limited by the scope (sample size and locations).
These limitations of previous studies were addressed in a multisite study carried out by All India Institute of Medical Sciences, New Delhi, to assess the effectiveness of buprenorphine with the support of United Nations Office on Drugs and Crime. With a “pre-post” design, 231 opioid-dependent patients from five sites across the country were recruited and provided sublingual buprenorphine treatment. The retention rate was 79% at 3 months, 70% at 6 months, and 64% at 9 months, with a compliance rate of more than 80% among those retained in treatment. A significant reduction in drug use was observed – the mean number of days heroin used (24.9 ± 10.1 days) at baseline reduced to <2 days at 9-month follow-up assessment. Similarly, there was a significant reduction (P < 0.001) in injection use, which declined from 52% at baseline to 13% at 9 months. The scores in all the four domains (physical, psychological, social relationship, and environment) of “WHO Quality of Life” at 9 months showed an increase. Other studies carried out in small scale in the Northeast region also reported the similar findings and thus demonstrated the effectiveness of OST in India.
After methadone was available in India, a need was felt to examine its effectiveness and feasibility. Using a similar “pre-post” design, a multicentric study assessed the effectiveness of methadone maintenance treatment (MMT) across five centers in India. This report also showed a substantial reduction in drug use with MMT, with 80% opioid-dependent patients on methadone reporting abstinence from other opioids at 3-month follow-up.
Besides these studies with a prospective design, naturalistic, observational studies, based upon the chart review approach, have also been available from many parts of India, including from the tertiary care teaching institutions as well as community-based settings. In an important study comparing buprenorphine maintenance, naltrexone maintenance, and psychosocial interventions, Bandawar et al. 2015 reported the superiority of buprenorphine maintenance in treatment retention over other two treatment approaches. For treatment retention, the buprenorphine maintenance was 4.5 times more effective than naltrexone maintenance and seven times more than psychosocial intervention alone. A study that assessed the retention rates of patients maintained on buprenorphine over long period of time showed that 35% patients were retained at the end of 6 years in a community outreach clinic in New Delhi.
Apart from buprenorphine and methadone, slow-release oral morphine (SROM) has also been tried as OST in India. There have been two peer-reviewed publications on SROM as OST, reporting that all 34 patients initiated on SROM continued to use the medicines at the end of 4 weeks of observation, with good control of opioid withdrawal symptoms.,
However, in keeping with the much wider clinical usage of buprenorphine as compared to other opioid agonists, the Indian literature on effectiveness of OST has a preponderance of studies on buprenorphine. By and large, studies on the effectiveness of OST from India show similar trends as reported from other parts of the world. Indian studies on OST have demonstrated retention rates as well as reduction in opioid use, high-risk injecting behavior, and improvement in quality of life (QOL).
Dose Requirements of Opioid Substitution Therapy Medicines
The earliest studies of buprenorphine as a treatment agent in India focused on exploring whether buprenorphine can work to provide some relief to the patients of opioid dependence and if yes, what would be the appropriate dose. The early clinical experience as well as research work indicated that lower dose of buprenorphine (as compared to Western literature) would be required for maintenance treatment among Indian patients.
Earlier studies on buprenorphine have shown the high rates of retention even with low dose of buprenorphine. These studies used buprenorphine doses in the range of 1.2–2 mg/day. Notably, the only formulation of sublingual buprenorphine available during this period was 0.2 mg. The higher strengths of buprenorphine (0.4 mg and 2 mg) became available only in 2000. Exploration of appropriate dose has also been carried out using experimental designs. In a double-blind, randomized, controlled trial, 23 opioid-dependent patients were provided 2 or 4 mg buprenorphine sublingually. There was no significant difference in both the groups in terms of measures of euphoria, sedation, protracted withdrawal symptoms, side effects, craving, and overall well-being. The authors concluded that doses lower than those described in the guidelines from the developed countries would be sufficient for the Indian population.
The multicentric study on buprenorphine carried out in 2005–2007 reported a mean dose of 6 mg/day of buprenorphine. Similarly, the mean dose of buprenorphine used during this period for opioid-dependent patients in the two Northeast states of Manipur and Nagaland was also in the range of 4–8 mg/day. A situation assessment conducted among 42 OST centers, supported by National AIDS Control Organization (NACO), reported that the mean dose of buprenorphine was 6 mg/day and 89% patients reported that they were satisfied with the dose. The lower dose requirement of Indian patients is also reflected with methadone. The multicentric study on methadone also reported the average dose of methadone required for each patient to be 40 mg/day, a dose much less than the minimum recommended dose of 60 mg/day in most international studies and guidelines.
Even with low doses, the retention rates, rates of abstinence from opioids, and proportion of opioid withdrawals reported are comparable to international studies that have used higher doses of OST medicines. Going by the research evidence and practices followed, the Indian guidelines on buprenorphine and methadone advocate the lower maintenance doses than recommended in the guidelines from Western countries.,, However, the reasons for low dose among the Indian patients have not been ascertained till date.
Safety and Adverse Effects of Opioid Substitution Therapy Medicines
After grant of approval for the treatment of opioid dependence, every molecule has been subjected to a postmarketing surveillance (PMS) study as per the regulatory requirements. Thus, PMS studies have been conducted for higher strength formulations of plain buprenorphine, buprenorphine–naloxone combination, and methadone.,, The reports of the PMS provide a fair idea of the safety and adverse effects experienced by the Indian patients maintained on OST. All the three PMS studies show that serious adverse events are extremely rare. Most adverse effects reported by the patients could be attributed to either lower than or higher than optimal doses of the OST medicines. Thus, complaints of body aches, generalized weakness, craving, yawning, etc., could be attributed to low dose of OST medicines, while excessive sleepiness and constipation could be accounted for due to high dose of OST medicines.
Sexual dysfunction among the patients while on OST has been specifically examined. Ramdurg et al. reported that 83% patients maintained on buprenorphine reported at least one sexual dysfunction in their lifetime. However, it is not clear whether this is a side effect of buprenorphine or a comorbid condition association with opioid dependence.
Literature is also available on abuse potential of injection buprenorphine in India. Case reports documenting the existence of injection buprenorphine abuse started appearing in the last two decades of the last century. These publications, among the patients seeking treatment for their substance-use problems, reported sizable number dependent on buprenorphine.,, Most of these patients were using other opioids, commonly heroin, before graduating to injection buprenorphine. A recent study on the type of opioids used through injecting in India also reported pharmaceutical opioids to be the most common type, of which the most common group was injection buprenorphine. Notably, none of the clinical or epidemiological studies have found the evidence of “abuse” of sublingual buprenorphine tablets in a sizable number. Some studies have assessed the abuse liability of buprenorphine using an experimental study design. De et al. assessed the euphoria, drug liking, sedation, and subjective state of different opioids (buprenorphine, pentazocine, morphine, and distilled water) administered to opioid-dependent patients after detoxification. It was observed that buprenorphine behaved similar to morphine in all aspects rather than pentazocine or placebo. The study suggested that the abuse liability of buprenorphine is moderate rather than low. In another study, Singhal et al. assessed the subjective effects of additional doses of buprenorphine on patients already maintained on buprenorphine. It was seen that dysphoria and sleepiness increased with additional doses of buprenorphine, while euphoria and drug liking decreased. This effect was maximum at 10 mg dose of buprenorphine. The study concluded that the abuse liability of buprenorphine is low at higher doses.
Some case reports exist on psychosis associated with buprenorphine. A case report mentioned psychotomimetic effect of buprenorphine akin to “LSD-like trip.” A case report is of a middle-aged male developing psychosis induced by buprenorphine, while another report describes a 40-year-old, opioid-dependent male maintained on buprenorphine developing psychosis when his buprenorphine was stopped.
Other Substance Use during Opioid Substitution Therapy
OST is specifically aimed at treatment of opioid dependence. Thus, while studies on effectiveness of OST have reported reduction in use of opioids, some authors have specifically reported use of other, nonopioid substances along with OST.
In one study that assessed whether cannabis use influences OST-related outcomes among the buprenorphine-maintained patients, it was found that participants using cannabis were on lower doses of buprenorphine. There was no significant difference in the rates of opioid use or opioid withdrawals and craving between the two groups. Compliance to OST, number of days of employment, daily earning, and WHOQOL-BREF scores in all domains were comparable between those with and without cannabis use. Similarly, another study detected cannabis use through urine screening alone and found that there was no significant difference in cannabis detection rates between buprenorphine-positive and buprenorphine-negative samples. Pattern of alcohol use among the patients on OST was addressed in a study which assessed the effectiveness of brief interventions (BIs) for harmful alcohol use in opioid-dependent patients maintained on buprenorphine. Thirty-six (of 138 OST recipients screened) had assist scores in the harmful hazardous category at baseline. Of these, 35 patients underwent all the sessions of BI, and most of them reported significant influence of the BI on their alcohol use with reduction in their alcohol use.
Some studies have also reported high rates of comorbid tobacco use with OST, and few patients showing interest in quitting their tobacco use.,
Effectiveness in Different Settings/populations
The studies reviewed earlier in this article have been conducted largely in conventional clinical settings with largely adult male populations. However, some Indian literature also exists documenting OST in prison settings as well as for females and adolescents.
In the pilot study conducted to assess the feasibility and effectiveness of buprenorphine as OST in prison settings (in the Tihar prison of New Delhi), a total of 220 opioid-dependent prisoners were initiated on buprenorphine. The retention rate was 98% while in prisons, with 100% compliance rate among those retained. During the course of study, the number of prisoners reporting injecting drug use was significantly reduced, corroborated by urine drug screening. However, there was high attrition rate after release.
While there are no studies from India, specifically on OST among the women dependent on opioids, there are some case reports on the use of buprenorphine in pregnant women. In all the cases, the women conceived while they were maintained on OST and had had uneventful delivery, with no signs of neonatal abstinence syndrome among the babies delivered., The recent OST guidelines from NACO have also recommended the use of OST (both buprenorphine and methadone) in pregnancy and breastfeeding.,
In the adolescent opioid-dependent population too, while there are no specific studies on OST, a case report does mention successful maintenance of an opioid-dependent adolescent on buprenorphine for a 2-year period, with a history of poor outcome on naltrexone maintenance. Notably, most of the recent guidelines do not specifically prohibit the use of buprenorphine as OST in adolescence.,,
Opioid Substitution Therapy: Perspective of Patients
Some studies have tried to explore the perspective of patients receiving OST. A study from two tertiary care hospitals at Punjab assessed the attitude of the patients maintained on OST for at least 3 months, toward the medication. They found that even though more than 90% of patients felt that buprenorphine reduced craving and provided a normal life, 80% wanted to stop it. The most common reason cited was that daily visits to the clinic were a challenge for them and around 40% had the misconception that buprenorphine itself was an addiction. Another study conducted in another tertiary care hospital in India found that around one-third of the patients feared becoming dependent on buprenorphine, while around 82% reported that buprenorphine was most beneficial in control of withdrawals.
Summary and Conclusion
A considerable amount of research evidence exists in India on OST. It also appears that Indian researchers have made an attempt to address the various facets of OST, beyond establishing its effectiveness and safety. The challenges in scale-up for OST, as described in a recent editorial of this journal emanate not only from any lack of evidence base but also largely from the absence of a conducive policy environment. However, at the end of this review, some of the questions which need to be answered by further research have been listed below.
Comparing buprenorphine with methadone
While we know that both buprenorphine and methadone are beneficial in terms of retention, there are no direct comparisons between the two medications in terms of effectiveness and retention. In addition, it would be beneficial to know which subgroup of opioid-dependent patients would benefit more from a particular OST medicine.
Opioid substitution therapy in special populations
We do not have literature on considerations during providing OST in special population groups such as women and adolescents. Although literature from other countries shows equal benefits, it would be worthwhile to understand various aspects of OST in relation to special population groups in India.
Understanding dosage issues of opioid substitution therapy medicines
Although we have studies documenting benefits even with lower than Western settings doses in Indian patients, there is a need to understand why do Indian patients require lower doses. In this regard, placebo-controlled trials, pharmacogenomic studies, etc., can help to understand the reasons.
Understanding barriers to scale-up opioid substitution therapy
Although this treatment modality is in existence for more than two decades, we need to know more about the various barriers that hinder the availability and accessibility of OST. These barriers may be at the level of policy-makers, program managers, treatment providers, or the service recipients. Policy analysis of various laws and policies related to OST must also be undertaken to understand the gaps in policies and laws which can be plugged to make OST more available and accessible to those in need.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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