Buprenorphine-based opioid substitution therapy in

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VIEWPOINT

Buprenorphine‑based opioid substitution therapy in India: A few observations, thoughts, and opinions Abhishek Ghosh, Debasish Basu, Ajit Avasthi1

Department of Psychiatry, Drug De‑Addiction and Treatment Centre, PGIMER, 1Department of Psychiatry, PGIMER, Chandigarh, India

ABSTRACT

The most evidence‑based treatment for opioid dependence is opioid agonist maintenance treatment also known as opioid substitution therapy (OST). However, there are some critical, yet unaddressed issues of buprenorphine‑based substitution therapy, especially in the Indian context. These comprise of generalizability of the evidence for OST, especially for natural and pharmaceutical opioids and for all age groups, optimum dose and duration of OST, and mode of treatment delivery including the frequency of dispensing. Notwithstanding the use of buprenorphine‑naloxone combination, abuse and diversion are serious but often underreported problems. There is an urgent need for health services research in India on OST, focusing on these aspects. Rather than directly copying from Western models, it is important to try to understand the useful and safe program and policy options likely to be applicable in the Indian setting, with our own assets as well as vulnerabilities. Key words: Abuse, buprenorphine, diversion, opioid substitution therapy, recovery

INTRODUCTION According to the latest World Drug Report, there were 34 million opioid and 19 million opiate users across the globe. Although in terms of mere magnitude of users, the opioid is surpassed by cannabis (192 million), in terms of the enormity of the problems such as the drug‑related mortality and contribution to the disability‑adjusted life years, opioids score overall other illicit drugs.[1,2] Shifting our focus from the global to local scenario, as per the National household survey (2004), there were 2 million opioid users and 0.5 million with opioid dependence.[3] Being a household survey, underestimation of the actual Address for correspondence: Dr. Abhishek Ghosh, Department of Psychiatry, Drug De‑Addiction and Treatment Centre, PGIMER, Chandigarh, India. E‑mail: [email protected] Access this article online Quick Response Code Website:

size could be speculated. Moreover, going with the global trend, the number of users might have seen a substantial rise by now. Therefore, it would not be imprudent to say, in India, there is an enormous treatment need to cater to people with opioid dependence. The most evidence‑based treatment for opioid dependence is opioid agonist maintenance treatment, also known as opioid substitution therapy (OST). Methadone and buprenorphine are the two most common opioids used in OST. Indian experience with buprenorphine‑based OST is more than two decades old now. Recently, there has been a call for scaling up OST in India and placing it within the ambit of public health policy.[4,5] While we entirely and strongly endorse this call in principle, we would also This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected]

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DOI: 10.4103/psychiatry.IndianJPsychiatry_218_17

How to cite this article: Ghosh A, Basu D, Avasthi A. Buprenorphine-based opioid substitution therapy in India: A few observations, thoughts, and opinions. Indian J Psychiatry 2018;60:361-6.

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Ghosh, et al.: Opioid substitution therapy in India

like to share our observations, thoughts, and opinions in a few areas. Here, we intend to discuss some critical, yet unaddressed issues of buprenorphine‑based substitution therapy, relevant to the Indian context. GENERALIZABILITY OF THE EVIDENCE FOR OPIOID SUBSTITUTION THERAPY The existing evidence supports the efficacy of substitution therapy with regard to the improvement in treatment retention, reduction in illicit opioid use, improving quality of life, on one hand, and reducing the incidence of infection with human immunodeficiency virus (and possibly hepatitis C virus [HCV]), mortality, and possible reincarceration, on the other hand.[6‑10] All these have helped OST to be established as one of the harm reduction strategies. A closer examination of the evidence would reveal, however, that most of the evidence for OST comes from the treatment of heroin dependence.[6] Evidence of buprenorphine‑based treatment for opium dependence and dependence on pharmaceutical opioids are less robust because of inadequate number of studies with strong research design.[11,12] In India, both national and state‑level surveys reported a sizeable proportion of current users (nondependent and dependent) of natural opioids (opium and poppy husk).[3,13] Another substantial minority is reported to use low‑potency pharmaceutical opioids (such as diphenoxylate and tramadol).[13] Earlier published studies on OST in India too had samples with overwhelming preponderance of heroin and/or injection drug users (e.g., 92% of subjects of the study sample were heroin users in the study by Dhawan and Chopra, 2013).[14] Although an emerging evidence base for the treatment of prescription opioids with buprenorphine‑based OST is accumulating over the years, evidence is exclusively confined to high‑potency prescription opioids (such as hydrocodone and oxycodone).[15‑17] These findings are unlikely to be relevant for the low‑potency pharmaceutical opioid users of our country. Therefore, in India, blanket prescription of buprenorphine‑based opioid substitution for opioid dependence needs to be evaluated critically. We recommend individualized treatment decision for opium and low‑potency pharmaceutical opioid dependence. A recent systematic review had even reported some efficacy and safety of tincture of opium, at least in the short term.[18] This evidence must be interpreted with caution because some may advocate the legal availability of opium as a strategy to deal with the illicit use of opioids. Overall, more methodologically rigorous research is needed for the treatment of opium and low‑potency pharmaceutical opioid dependence. Recently, a stepped‑care treatment approach has been advocated for prescription opioid dependence in Canada, where agonist maintenance is considered 362

exclusively for nonresponders to less intrusive treatment that includes short‑term detoxification and psychosocial management.[19] In India, the treatment of dependence on low‑potency pharmaceutical opioids and natural opioids could be planned in the similar lines. However, we must acknowledge that before such recommendations, the stepped‑care plan should be tested for its effectiveness in the Indian context. In other words, OST should not be seen as a “one‑size‑fits‑all” approach for each and every case of opioid dependence. We must realize that treatment with antagonist‑like naltrexone (both oral and long‑acting injection) has reasonable research backing.[20‑22] Therefore, the choice of treatment, along with the evidence base, should also take into account the severity of dependence, complications of dependence, past treatment history, risk level for blood‑borne viral and other infections, and importantly, patient’s own choice, and considerations. Another group of patients, for whom OST evidence is uncertain, is the adolescents.[23] The Australian guideline for Medication‑Assisted Treatment of Opioid Dependence (MATOD) recommends family‑based and other psychosocial intervention for adolescents as the first treatment modality and suggests lesser duration (as compared to the adults) of opioid substitution as the second choice.[24] Currently, we do not know the magnitude of opioid dependence among adolescents in India; however, the aforementioned caveat must be kept in mind before implementing OST at a mass scale. Basically, the point which we want to make is, there should be an expanded menu of options for the treatment of opioid dependence, and treatment should be tailor‑made rather than the “one‑size‑fits‑all” approach. Drawing an analogy from Russia where agonist maintenance is not available, the experience with naltrexone is quite encouraging and has been attributed to the presence of stronger family control.[25] In India, where family involvement is the norm, antagonist treatment appears to be a promising option at least in selected cases. Indeed, one earlier study from our center did find naltrexone reasonably effective and acceptable to our opioid‑dependent patients.[26] Group of patients, where the use of naltrexone could be encouraged, is those with comorbid alcohol dependence. For this particular group, OST could be harmful, given the risk of CNS depression and mortality.[27] The notion of Indian culture as “dry” or “abstinent” is receding very fast, social acceptance of alcohol has gained considerable momentum.[28] Therefore, in our opinion, the proportion of people suffering from both alcohol and opioid dependence would rise in the foreseeable future, increasing the scope of naltrexone as the treatment option. In fact, the recent guideline, published by the American Psychiatric Association recommends the same.[29] Indian Journal of Psychiatry Volume 60, Issue 3, July-September 2018



CONTROVERSY REGARDING THE DOSE AND DURATION OF OPIOID SUBSTITUTION THERAPY It is now widely acknowledged that an average Indian patient might need lower dose of buprenorphine than his Western counterpart.[30] However, some authors suggested the use of higher dose of buprenorphine even in India, with an assumption that it would improve treatment retention and reduce the use of illicit drugs.[5] Although the literature from elsewhere suggests higher dose buprenorphine might be better than lower dosage, in our opinion, before generalizing the results, indigenous randomized controlled trials must be conducted.[6] Till such time, we recommend individualized, flexible dosing with a caution when the dose exceeds the usual range. We must realize that prescribing higher dose might increase the possibility of diversion.[31] It is interesting to note in this regard that one of the “first‑generation” Indian studies that utilized very low doses of buprenorphine of 1.2 mg– 1.8 mg (2 mg preparation was not yet available at the time of the study was conducted; only 0.2 mg was available) actually reported a very high patient retention rate of 81% at 6 months. Clearly, at least in the Indian scenario with its own sociocultural and family support system, there are factors other than only dose size that influences patient retention and outcome. The second related controversy which centered on OST is the duration of treatment. Although the evidence suggests the discontinuation of OST increases the potential for relapse and even mortality, lifelong, time‑unlimited OST might not be the answer for the same.[17,32] In India, time‑unlimited OST would impose a huge burden on already limited health‑care resources. Moreover, in longitudinal observational studies, it has been seen that only a fraction of clients could be retained in the treatment for 1 year.[33] The exposure to OST seems to be an episodic phenomenon. Taking cognizance of all these facts, we recommend “Recovery‑Oriented” practice. By the recovery‑oriented OST,[34] we mean, 1. Personal recovery as final goal (reintegration of the person with opioid dependence into the family and society and ensuring functional independence) 2. Objective goals would be decided by the persons themselves 3. Periodic evaluation of the recovery goals 4. OST should not be either time‑limited or time unlimited, rather would be “goal‑directed:” patients would be offered to discontinue OST after the predetermined goals (“recovery”) have been achieved, and the decision to come off OST should be mutually agreed 5. There would be a tentative time target of 1–2 years in which the person is expected to reach the goal of recovery, however, with the realization that it may not always be feasible Indian Journal of Psychiatry Volume 60, Issue 3, July-September 2018

6. Even after the discontinuation of OST, psychosocial interventions will still be at place and other medical support would also be provided if deemed necessary 7. Periodic posttherapy assessments would be done. Although these components are not something novel and have been advocated by other authors as well, these components are central to recovery‑oriented OST. The unique features of this OST are, it is neither time limited and rigid nor is it time unlimited and arbitrary. It would start with definitive long‑term goals in mind and with a tentative deadline to achieve those to keep the patient’s motivation alive. CONTROVERSY REGARDING TREATMENT DELIVERY According to a recent guesstimate, in India, only about 5% of people with opioid dependence receive OST,[5] which is much lower than the figure in Australia (50%), for example.[24] Hence, it seems imperative to scale‑up the existing OST program which is predominantly run by psychiatrists in government de‑addiction centers, and national AIDS control organization‑based NGOs.[4] To do so, the concept of physician‑assisted opioid treatment delivery has been suggested. This is not a novel idea and is practiced across the US, Europe, and Australia. We wish to discuss some crucial points regarding the physician‑assisted treatment. First, we must ensure those who prescribe buprenorphine must be rigorously trained and certified. There must be an initial cap in the number of patients they would be able to treat, which later could be extended following periodic appraisal. The office‑based opioid treatment (OBOT) in the US follows a similar guideline.[35] In India, the medical officer cadres, who are usually medical graduates (MBBS), are not at all exposed to the treatment of addictive disorders.[36] In fact, the standard and quality of training during MD, Psychiatry residency is also questionable. In this background, training the physicians for the treatment of opioid addiction is not an easy task, to be accomplished in a 7 day or so program. Implementing such practice would call for identifying the training institutes, trainers, training manuals, hands‑on training centers, certifying, and regulating bodies. At present, no such recognized bodies exist in India. Second, the standalone prescription of buprenorphine is not enough. The OBOT program of the US ensures the affiliation of OBOT to a formal opioid treatment agency where the patients are referred for psychosocial intervention.[24] In the Canadian model, patients participate in community‑based psychosocial care.[37] Therefore, the need for an additional nonpharmacological intervention cannot be undermined, while scaling up OST, we must emphasize this need and guarantee adequate psychosocial 363



support by trained workforce (which may also include the prescribing physician). An optimal psychosocial intervention consists of initial psychoeducation, management of craving, imparting stress, anger management, problem‑solving skills, and relapse prevention. The psychosocial intervention is not merely aimed at abstinence from illicit opioid use; it envisages occupational rehabilitation and reintegration of the person within the family and society. We believe that the psychosocial intervention would play a paramount role in recovery‑oriented OST and recommend it to be an integral part of an OST program. THE RISK OF ABUSE AND DIVERSION This is widely documented. Abuse is defined by any use of the prescription drug that deviates from the medical practice. Common examples of the same would be injecting the sublingual preparation or taking more than the prescribed dose. Diversion is understood as unauthorized rerouting or appropriation of the drug.[38] Buprenorphine was thought to have lower abuse potential than methadone, but with its growing use, the abuse of buprenorphine came to the notice.[39‑41] To deter people from injecting sublingual buprenorphine, it has been combined with naloxone (BNX). It was conjectured that such combination would have less potential for abuse or diversion. A postmarketing surveillance from Australia reported the lower incidence of injection of prescription drugs in the BNX group as compared to the plain buprenorphine group. However, the injection use was comparable with methadone.[42] A report from Malaysia also showed widespread BNX injection use, although it was lesser than pure buprenorphine.[43] Data from Australia showed buprenorphine diversion as high as 15% in the year 2005, and it was more than methadone.[38] Reports from Baltimore stated that about 10% of people with opioid dependence reported street‑obtained buprenorphine use, which is a direct indicator of diversion.[44] Report from Sweden states a much higher figure of 24% diversion in the past month and more than 60% lifetime diversion; rate was higher for plain buprenorphine.[45] Therefore, it is quite clear that neither buprenorphine nor BNX is resistant to either abuse or diversion. In fact, a recent expert consensus from Europe and UK has made an emphatic point regarding abuse and diversion of agonist treatment, and the direct and indirect health, social, and economic effects. Addressing the problem by defining the strategies of OST delivery, for reducing the abuse and diversion is needed, rather than endless expansion of the existing system.[46] In a review of Larance et al. cautions, “India is believed to account for significant large‑scale diversion within the region (South Asia) and further afield through poor regulation of illicit opioid production and pharmacies.”[47] All these evidence make us concerned and tell us to tread our path cautiously. With the zeal to scale‑up OST, we must not lose our sight to this flip side and must make every attempt to prevent abuse and diversion. 364

At the same time, it must be mentioned that creating high barriers for OST services is also a known factor for OST drug diversion because then patients use it for self‑medication or as a general substitute while waiting for the services.[39,48] Thus, both underexpansion and careless overexpansion of OST can be harmful. Patient characteristics which were identified for increasing the risk of abuse or diversion included history of injection use, younger age, contact with prison, and having drug‑using social circle.[45,49] Hence, these groups of patients need special monitoring. We recommend regulated prescription from accredited (trained and certified) physicians, proper documentation, periodic appraisals, and definite accountability for OST. In India, we have an additional and very useful support: the family. The family must be utilized by encouraging the involvement of family members in all phases of treatment. We believe that this endeavor might reduce the chance of abuse and diversion. We are aware that all these sound quite cumbersome; however, we are of the opinion that such rigorousness is required to prevent any unwarranted disrepute to this otherwise excellent, evidence‑based treatment for opioid dependence. FREQUENCY OF OUTPATIENT VISITS OST started with directly observed treatment. However, with the advent of physician‑assisted OST, OST from primary care and availability of BNX and take‑home doses are approved by the drug policies of the UK, Australia, and other countries.[50,51] However, there is a dearth of literature in this area. The available literature shows there is no difference in terms of treatment retention and illicit drug use between directly observed treatment and weekly pickup group; however, the latter has significantly more chances of abuse and diversion.[52] Instances of snorting buprenorphine have also been reported in another study.[53] Nevertheless, the treatment cost of takeaway program was much lesser than daily dispensing. In view of the problems of limited resources but the strength of the available family support, we recommend take‑home dosage during the maintenance phase of OST, not during the induction phase. The frequency of dispensing might be once or twice per week, depending on the resources, and the individual’s risk of misuse‑diversion. In addition, we believe, only buprenorphine‑naloxone is to be used to take home to reduce the chance of abuse and diversion. CONCLUDING COMMENTS Scaling‑up OST is important and must be done, but with caution and acknowledging its limitations. History should teach us in this regard, providing an opportunity to learn from many countries worldwide but particularly from Indian Journal of Psychiatry Volume 60, Issue 3, July-September 2018



Malaysia (with relatively similar background as India) where the liberal office‑based treatment with buprenorphine, predominantly by minimally trained general practitioners, ushered an epidemic of injection buprenorphine abuse. This epidemic, although contained, continued in a substantial proportion despite improvement in training of practitioners and replacing buprenorphine with buprenorphine‑naloxone combination, although even the latter was misused. The most important source of abused buprenorphine was general private practitioners.[43] From worldwide, history teaches us that OST is a double‑edged sword: public harm is caused when there are high barriers to OST by forcing users to continue the use of much more harmful illicit drugs and/or injecting practices, or to (mis) use OST medication often as self‑medication. On the other hand, there is ample evidence that unrestricted availability of any opioid – and that includes the OST medications – increases their chances of abuse and diversion. There is an urgent need for health services research in India on OST, focusing on various aspects mentioned in the above sections. Rather than directly copying from Western models, it is important to try to understand which are the useful and safe program and policy options likely to be applicable in the Indian setting, with our own assets (e.g., relatively strong family support, relatively lower potency of both illicit and prescription opioids than in the Western countries, and relatively more social stability) as well as vulnerabilities (e.g., lax monitoring system, poor accountability, and physician incentives in the private sector). In the absence of such research evidence, many of the opinions expressed in this article must be seen as tentative and may need revision in the future based on health service research data. However, we believe that the value of this opinion article lies in highlighting several important yet unaddressed issues relevant to OST scale‑up proposals in India.

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Indian Journal of Psychiatry Volume 60, Issue 3, July-September 2018