Tapentadol, the new kid on the block in India: Is it time to worry?

BACKGROUND AND OBJECTIVES: Large-scale prospective case series of tapentadol abuse or dependence in India is not available. Hence, we aimed to study the prevalence and profile of tapentadol users in a treatment-seeking population.
MATERIALS AND METHODS: The study had prospective and retrospective arms. We collected 8-month prospective data by face-to-face interviews (n = 70) and 8-year retrospective data from case notes (n = 26) with either tapentadol misuse/abuse or dependence in patients attending a de-addiction center.
RESULTS: The prevalence of tapentadol abuse or dependence was 25% among the pharmaceutical opioid users. Concurrent use of other opioids was seen in >80% of participants of both the arms. Major sources of tapentadol were chemists (without a prescription) (53%) and doctors (prescriptions) (40%). Patients in the tapentadol dependence group had a significantly higher dose, duration, and pharmaceutical opioid use.
CONCLUSION: India needs awareness promotion, training, availability restriction, and provision of treatment for tapentadol abuse or dependence. Copyright:

INTRODUCTION

The 2019 Magnitude of Substance Use in India survey showed pharmaceutical opioids to be the second most commonly abused opioids (0.96%), after heroin (1.14%).[1] After scheduling of codeine, dextropropoxyphene, and tramadol due to their abuse potential in 2011, 2017, and 2018, respectively, there is a chance of emergence of abuse of another new pharmaceutical opioid.

Tapentadol is a synthetic opioid with both μ-opioid receptor agonist and selective serotonin reuptake inhibitor actions. The μ-receptor agonism of tapentadol lies in between that of morphine and tramadol.[2] Although tapentadol has not yet been scheduled under the Narcotic Drugs and Psychotropic Substances Act, there is emerging clinical experience and initial evidence showing its abuse liability in India. Basu et al. reported two patients who substituted dextropropoxyphene and buprenorphine with tapentadol.[3] A recent retrospective study published from southern India described the sociodemographic and clinical profile for patients seeking treatment for tapentadol dependence. This study also used Google search Trend as a proxy marker for interest in tapentadol, which showed that the union territory of Chandigarh (CG) was in the forefront regarding the online interest of tapentadol.[4] However, the retrospective study design has flaws such as recall bias and reduced availability of information. Moreover, substance use patterns in India differ across regions.[1] Addressing these limitations and tapping the regional difference required another study. We aimed to study the prevalence and profile of tapentadol users in a treatment-seeking population in North India using a mixed design.

MATERIALS AND METHODS

We aimed to examine the prevalence and sociodemographic as well as the clinical profile of tapentadol users attending an addiction treatment facility of a tertiary-care teaching general hospital's psychiatric unit in CG. We used a uniform semi-structured evaluation format to assess patients. An in-house laboratory provided urine drug screening. Ethical clearance was obtained from the institute's ethics committee for this study.

This study had a prospective arm (PA; May to December 2019) and another retrospective arm (RA; July 2011 to April 2019). We included all the patients with reported or recorded history of tapentadol use.

Operational definitions

Dependence was diagnosed as per the International Classification of Diseases-10 (ICD-10) criteria.[5]

Misuse was defined as any use outside of prescription parameters, including misunderstanding of instructions; self-medication of sleep, mood, or anxiety symptoms; and compulsive use driven by an opioid use disorder.[6]

Abuse was defined as use without a prescription, in a way other than prescribed, or for the experience or feelings elicited.[6]

Procedure

For the RA (July 2011–April 2019), we extracted the case records with the ICD-10 diagnosis of opioid dependence, and after a manual check of the case notes, we recorded the specified sociodemographic and clinical parameters of those with tapentadol use/dependence. For the PA (May 2019–December 2019), we recruited all first-visit patients from the walk-in clinic who acknowledged tapentadol use after obtaining informed consent. The dose, duration of consumption, route, brand, and formulation of tapentadol used were recorded in both the arms. We recorded further details such as the reason of use, psychoactive effect, and source of the substance while directly interviewing the patients in the PA.

Statistical analysis

We applied descriptive statistics (mean with standard deviation wherever applicable) for both the arms. Subsequently, we compared the means of sociodemographic, clinical, and tapentadol-related variables between the two subgroups of the PA (misuse–abuse [MA group] and dependent group) to determine if there were significant intergroup differences.

RESULTS

From May to December 2019, there were a total of 3084 new cases, including 1860 cases with opioid dependence. There were 279 cases with pharmaceutical and/or mixed opioid use and 70 cases of tapentadol use. The prevalence of tapentadol use was 2.3% among all new cases, 3.8% among opioid users, and 25.1% among pharmaceutical/mixed opioid users [Figure 1]. We could identify only 26 cases of tapentadol use in the RA. The first case was recorded in November 2014. We could find two cases each from the years 2015 to 2017, 14 cases in 2018, and 5 cases from January to April 2019.

Figure 1

Prevalence of tapentadol use among the patient population

Sociodemographic and clinical variables of patients

Both the arms predominantly consisted of young, unmarried, unemployed males, who were educated up to intermediate and were hailing from nuclear families, urban background, and adjacent areas [Table S1]. On an average, patients started using opioids in their early twenties and were using the same for around 6 years. Tapentadol use started in their mid-twenties and continued for around 1–2 years with a daily average dose of around 550 mg. Nearly half of the PA patients used heroin (around one-fourth had morphine-positive urine) and around one-third of the RA patients used tramadol (around one-fourth had tramadol-positive urine) concurrently. Although most of them had a history of intravenous opioid use, only four patients in PA arm used intravenous tapentadol. “Tapal” was the most familiar brand, and “immediate release” was the most common preparation used by our patients. Around half of the patients were nicotine dependent. Around one-third of the patients had no prior treatment history. Five patients were hepatitis C positive; 11 had a psychiatric illness (most commonly mood disorder) and 21 patients had medical comorbidities [Table 1].

Table S1

Sociodemographic data of patients in prospective and retrospective arms

Variables	PA (n=70), n (%)/mean (SD)	RA (n=26), n (%)/mean (SD)
Mean age (years)	27.36 (6.44)	29.46 (6.75)
Sex
Male	69 (98.6)	25 (96.1)
Female	1 (1.4)	1 (3.9)
Marital status
Never married	41 (58.6)	15 (57.7)
Married	26 (37.1)	10 (38.5)
Separated and divorced	3 (4.3)	1 (3.8)
Education
Illiterate	1 (1.4)	2 (7.6)
Up to matriculation	18 (25.7)	9 (34.6)
10, +2/diploma	34 (48.6)	8 (30.8)
Graduate and above	17 (24.3)	7 (27.0)
Occupation
Professional and semi-professional	8 (11.4)	1 (3.8)
Clerical/shop owner/farmer	12 (17.1)	5 (19.2)
Skilled worker	11 (15.7)	4 (15.4)
Semi-skilled worker	10 (14.3)	3 (11.5)
Unskilled	2 (2.8)	1 (3.8)
Unemployed	27 (38.6)	12 (46.2)
Family type
Nuclear	40 (57.1)	19 (73.1)
Joint/extended	30 (42.9)	7 (26.9)
Locality
Urban	52 (74.3)	16 (61.5)
Rural	18 (25.7)	10 (38.5)
Distance
Local	29 (41.4)	11 (42.3)
Up to 40 km	21 (30.0)	8 (30.8)
40-80 km	7 (10.0)	3 (11.5)
>80 km	13 (18.5)	4 (15.4)

PA – Prospective arm; RA – Retrospective arm

Table 1

Clinical data of patients in the prospective and retrospective arms

Variables	PA (n=70), n (%)/mean (SD)	RA (n=26), n (%)/mean (SD)
Age of first use of opioids (years)	22.7 (5.03)	23.77 (5.01)
Duration of dependence (months)	52.81 (52.73)	59.54 (62.14)
Age at first use of tapentadol (years)	26.41 (6.63)	24.42 (5.61)
Duration of use (months)	10.33 (9.61)	20.58 (16.25)
Average daily dose (mg)	526.29 (475.77)	565.22 (462.80)
Concurrent opioid use
None	11 (15.7)	5 (19.2)
Natural	7 (10.0)	2 (7.7)
Heroin	32 (45.8)	4 (15.4)
Tramadol	16 (22.9)	10 (38.5)
Others	4 (5.6)	5 (19.2)
Urine testing
Not available	0 (0)	11 (42.3)
Opioid negative	15 (21.4)	2 (7.7)
Tramadol positive	12 (17.1)	6 (23.1)
Morphine positive	17 (24.3)	6 (23.1)
BPN positive	3 (4.3)	1 (3.8)
Intravenous opioid use
No	39 (55.7)	22 (84.6)
Yes	31 (44.3)	4 (15.4)
Route of tapentadol use
Oral	67 (95.7)	26 (100)
Parenteral	3 (4.3)	0 (0)
Formulation
Unknown	7 (10.0)	12 (46.2)
Instant release	61 (87.1)	9 (34.6)
Sustained release	1 (1.4)	3 (11.5)
Both	1 (1.4)	2 (7.7)
Brand name
Unknown	15 (21.4)	18 (69.2)
Tapal	37 (52.9)	6 (23.1)
Others	18 (25.7)	2 (7.7)
Past opioid use
None	8 (11.4)	4 (15.4)
Natural	19 (27.1)	2 (7.7)
Heroin	22 (31.4)	5 (19.2)
Tramadol	10 (14.3)	5 (19.2)
Others	13 (18.6)	10 (38.4)
History of other drug dependence
None	14 (20.0)	4 (15.4)
Alcohol	4 (5.7)	2 (7.7)
Cannabis	18 (25.7)	2 (7.7)
Benzodiazepine	5 (7.1)	3 (11.5)
Nicotine	29 (41.4)	15 (57.7)
Past history of treatment seeking
Nil	24 (34.3)	12 (46.2)
Government centers	12 (17.2)	3 (11.5)
Private centers	34 (48.5)	11 (42.3)
HCV status
No	66 (94.3)	25 (96.1)
Yes	4 (5.7)	1 (3.9)
Psychiatric illness
None	63 (90)	21 (84.6)
Present	7 (10)	4 (15.4)
Medical comorbidity
No	58 (82.9)	17 (65.4)
Yes	12 (17.1)	9 (34.6)

SD – Standard deviation; BPN – Buprenorphine; PA – Prospective arm; RA – Retrospective arm; HCV – Hepatitis C virus

Characteristics and pattern of tapentadol use in prospective arm

Most of the PA patients started tapentadol to substitute their usual opioid (71.4%), whereas nearly half of them (48.6%) were substituting heroin with tapentadol. Most (72.9%) of them considered the psychoactive effect of tapentadol to be inferior to their usual opioid. While 27 (38.6%) patients were prescribed tapentadol by a doctor at some point in time, 37 (52.9%) patients were buying tapentadol from a chemist without prescription. Half (51.4%) of the patients met the definition of MA group, and the rest met the criteria for dependence (D group) [Table 2].

Table 2

Characteristics and pattern of use of tapentadol among patients in the prospective arm

Variables	PA (n=70), n (%)
Probable reason for initiation of tapentadol
Substitute for the usual opioid	50 (71.4)
Pain management	2 (2.9)
Augmenting the psychoactive effect of the usual opioid	5 (7.1)
Started with tapentadol itself	6 (8.6)
Prescribed/took for withdrawal management	7 (10.0)
Substitution for opioid
None	8 (11.4)
Natural	8 (11.4)
Heroin (chasing and intravenous)	34 (48.6)
Tramadol	13 (18.6)
Others	7 (10)
Psychoactive effect of tapentadol
Better than usual opioid	4 (5.7)
Same to the usual opioid	6 (8.6)
Inferior to the usual opioid	51 (72.9)
Started with tapentadol only	8 (11.4)
Different	1 (1.4)
Was tapentadol prescribed by physician?
No	43 (61.4)
Yes	27 (38.6)
Possible current source of tapentadol
Friend	20 (28.6)
Chemist	37 (52.9)
Peddler	11 (15.7)
Other	2 (2.9)
Pattern of tapentadol use
Misuse/abuse	36 (51.4)
Dependence	34 (48.6)

PA – Prospective arm

Sociodemographic, clinical, and tapentadol-related variables in the subgroups of prospective arm

The MA and D groups were similar in their sociodemographic and clinical profile [Table S2]. Although both the groups had initiated tapentadol use at a similar age, the D group had significantly higher mean duration (13.7 ± 10.1 months) and daily dose (mean 820.3 ± 531.0 mg) of tapentadol. A significantly higher number of patients in the MA group were using heroin concurrently (69.4%), were using tapentadol to substitute heroin (63.9%), were prescribed tapentadol by a physician at some point of time (55.6%), and were buying it from a pharmacy (66.7%). A significantly higher number of patients in the D group considered the psychoactive effect of tapentadol to be noninferior (29.4%) than their usual opioid and had a comorbid psychiatric illness [Table 3].

Table S2

Comparison between sociodemographic and clinical variables between patients with misuse/abuse and those with dependence to tapentadol

Variable	Misuse/abuse (n=36), n (%)/mean (SD)/rank	Dependence (n=34), n (%)/mean (SD)/rank	Chi-square/Fisher’s exact/t/Mann-Whitney U-value	df	P
Mean age (in years)	27.1 (6.5)	27.6 (6.5)	−0.327	68	0.75
Marital status
Married	12 (33.33)	14 (41.18)	0.461	1	0.48
Not married	24 (66.67)	20 (58.82)
Education
Up to matric	8 (22.22)	11 (32.35)	1.064	2	0.59
10, +2/diploma	18 (50)	16 (47.06)
Higher	10 (27.78)	7 (20.59)
Occupation
Unemployed	16 (44.44)	11 (32.35)	2.236	2	0.33
Unskilled and semi-skilled	4 (11.11)	8 (23.53)
Skilled	16 (44.44)	15 (44.12)
Family type
Nuclear	21 (58.33)	19 (55.88)	0.043	1	0.84
Extended	15 (41.67)	15 (44.12)
Locality
Urban	29 (80.56)	23 (67.65)	1.525	1	0.22
Rural	7 (19.44)	11 (32.35)
Distance
Within CG UT	13 (36.11)	16 (47.06)	0.864	1	0.49
Outside CG UT	23 (63.89)	18 (52.94)
Age of first use of any opioids	23.5 (5.2)	21.9 (4.8)	1.353	68	0.18
Duration of dependence	48.9 (51.8)	57.0 (54.2)	657.0		0.60
Types of past opioid use
Natural	8 (22.22)	11 (32.35)	0.62	4	0.57
Heroine	17 (47.22)	5 (14.71)
Others (pharmaceuticals)	8 (22.22)	13 (38.24)
Intravenous opioid use
No	18 (50)	21 (61.76)	0.981	1	0.32
Yes	18 (50)	13 (38.24)
Past history of treatment seeking
Yes	23 (63.89)	23 (67.65)	0.741	1	0.80
No	13 (36.11)	11 (32.35)
History of other drug dependence
None	9 (25)	5 (14.71)	2.620	3	0.454
Nicotine	16 (44.44)	13 (38.24)
Cannabis	8 (22.22)	10 (29.41)
lcohol/BZD	3 (8.33)	6 (17.65)
Medical comorbidity
No	30 (83.33)	28 (82.35)	0.012	1	0.913
Yes	6 (16.67)	6 (17.65)

CG – Chandigarh; UT – Union territory; BZD – Benzodiazepine

Table 3

Comparison between patients with misuse/abuse and those with dependence to tapentadol with regard to characteristics and patterns of use of tapentadol

Variable	Misuse/abuse (n=36), n (%)/mean (SD)/rank	Dependence (n=34), n (%)/mean (SD)/rank	Chi-square/Fisher’s exact/t/Mann-Whitney U value	df	P
Age of onset of tapentadol (years)	26.5 (6.4)	26.4 (6.9)	0.075	68	0.941
Duration of use (months)	7.2 (8.1)	13.7 (10.1)	877		0.002
Daily dose (mg)	248.6 (130.8)	820.3 (531.0)	−6.264	68	<0.001
Route of use
Oral	36 (100)	31 (91.18)	3.319	1	0.109
Intravenous	0	3 (8.82)
Brand
Tapal	18 (50)	19 (55.88)	0.24	1	0.62
Others	18 (50)	15 (44.12)
Reason
Substitution	27 (75)	23 (67.65)	0.463	1	0.50
Other	9 (25)	11 (32.35)
Concurrent opioid use
Natural	4 (11.11)	3 (8.82)	10.828	2	0.004
Heroin	25 (69.44)	7 (20.59)
Others	6 (16.67)	13 (38.24)
Substitution of opioids
None	3 (8.11)	5 (14.71)	8.364	2	0.015
Heroin	23 (63.89)	10 (29.41)
Pharmaceutical and natural	10 (27.78)	19 (55.88)
Prescribed by physician
No	16 (44.44)	27 (79.41)	9.023	1	0.003
Yes	20 (55.56)	7 (20.59)
Source
Chemists	24 (66.67)	13 (38.24)	5.67	1	0.017
Friends and peddlers	12 (33.33)	21 (61.76)
Psychoactive effect of tapentadol
Inferior	35 (97.22)	24 (70.59)	9.365	1	0.002
Not inferior	1 (2.78)	10 (29.41)
Psychiatric illness
Absent	35 (97.22)	27 (79.41)	5.48	1	0.019
Present	1 (2.78)	7 (20.58)

SD – Standard deviation

DISCUSSION

We believe that this is the first prospective study from India on tapentadol abuse or dependence with a reasonably large sample. The PA of the study shows the prevalence of tapentadol abuse and dependence in the clinic, whereas the RA reflects an apparently increasing trend of use in the treatment seekers. Nearly 3/4th of the total 96 patients with tapentadol use were identified during the prospective study. It highlights the importance of proactive case finding and gathering additional relevant information (reason of initiation, subjective psychoactive effect, etc.) for better case profiling in patients with an emerging substance of abuse.

Majority of the PA patients were using tapentadol as a substitute for the usual opioids. This result, in contradiction to that of a recent study from southern India,[4] might reflect either different opioid use profile or treatment-seeking pattern in the community. Previous studies from our region reported heroin and natural opioids as the most common opioids of abuse.[789] Thus, tapentadol could be responsible for sustaining opioid use during the period of nonavailability of illicit opioids. This assumption is supported as most of the patients were using immediate-release preparation and were procuring the same from pharmacies that illegally dispense tapentadol without a prescription. Mukherjee et al. reported similar results.[4]

The other clinically important finding from this study is that nearly half of the tapentadol users fulfilled the dependence criteria of ICD-10, which is in line with the findings of Mukherjee et al.[4]

Univariate analysis revealed a higher dose, longer duration, and report of a “noninferior high” of tapentadol use in the dependent group. This finding has indirect literature support. Concomitant opioid dependence was found to be the most significant risk factor for developing a dependence on prescription opioids.[10] A summary of 67 studies revealed that on an average, 22 months of prescription opioid exposure was necessary to develop opioid dependence among patients with chronic pain.[11] The differences in population might explain relatively shorter mean duration (~14 months) of tapentadol use in the D group. The significantly higher psychiatric comorbidity in the D group is in line with the findings of a systematic review, showing that prescriptions of psychotropic medications had increased and absence of major depressive episode had decreased the risk of opioid addiction among prescription opioid users.[10]

The varying source of tapentadol in the subgroups is an interesting finding. Research suggests that difference in sources may be related to motivation for use. A study among street-based drug users of New York reported drug dealers as the predominant source of oxycontin in users taking it to get “high,” whereas those taking oxycontin for pain would primarily get it from the pharmacies.[12]

Around 40% of cases were prescribed tapentadol by a doctor, possibly to treat withdrawal symptoms. This practice raises concern for diversion and use of nonevidence-based treatment for opioid dependence. Volkow and McLellan asserted that in the USA, the major source of diverted pharmaceutical opioids was physicians' prescription.[13] A reason for nonevidence-based prescriptions could be the overt legal restriction on the availability of opioid agonist treatment in India.[14] Therefore, we should ensure physicians' education and awareness, prescription monitoring, and improved access and availability of evidence-based treatment to address the problem.

There were some limitations to the present study: (1) the findings may not be generalizable to the community; (2) longitudinal data would help to predict the use pattern; and (3) the disproportionately less number of patients in the RA suggests that a large number of cases might have been missed.

CONCLUSION

With its unrestricted availability, tapentadol is causing concern among medical professionals in India as it is emerging as a substitute for illicit pharmaceutical opioids. Both from the policy and the clinical perspectives, India needs awareness promotion, training, availability restriction, and provision of treatment for tapentadol abuse or dependence.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.