Is tapentadol a potential Trojan horse in the postdextropropoxyphene era in India?

Tapentadol is a centrally acting opioid analgesic which has partial opioid agonistic and norepinephrine reuptake inhibitor action similar to its nearest congener and tramadol though with a relatively higher μ-affinity. It has abuse potential, is a scheduled drug, yet currently is not known to be an opioid widely misused in India. However, under the current drug abuse legislation in India, where common prescription opioids such as dextropropoxyphene have been banned, tapentadol may take the center stage of pharmaceutical opioid abuse in the near future. We present a series of two cases where the opioid use started with codeine, dextropropoxyphene, and buprenorphine but moved on to tapentadol and tramadol due to ease of access and cost. These cases highlight the potential of tapentadol in replacing dextropropoxyphene as the widespread prescription opioid of abuse and also emphasize the current controversies regarding opioid control policies in India.

Introduction

Tapentadol hydrochloride is a centrally acting analgesic useful in the treatment of both acute nociceptive and chronic neuropathic pain. Chemically, 3-[(1R,2R)-3-(dimethylamino)- 1-ethyl-2-methylpropyl] phenol hydrochloride is a nonracemic molecule unlike its nearest congener and tramadol which is a racemic mixture of different enantiomers.[1] Tapentadol combines relatively strong μ-opioid receptor agonism with norepinephrine reuptake inhibition. Due to this dual action, though it has one-fiftieth the affinity to the murine μ-opioid receptor, its analgesic potency is one-third when compared with morphine. Bioavailability of the drug is 32% and only 20% is bound to plasma proteins. Its half-life is of 4.9 h and it is mostly eliminated through renal elimination through glucuronide conjugation. Moderate hepatic dysfunction warrants dose reduction. Studies show that with tapentadol, there are minimal drug-drug interactions. Since it is a noradrenaline reuptake inhibitor, it is relatively contraindicated in patients receiving monoamine oxidase inhibitors in the past 14 days.

In human double-blind randomized controlled trials, it has been shown to have significant efficacy in patients with third molar extraction, bunionectomy, and degenerative joint disease, making it suitable for the treatment of severe pain (WHO pain ladder Step 3).[2] The common adverse effects are sedation, dizziness, constipation, pruritus, respiratory depression, and significant abuse potential as per animal and preliminary human studies. In India with the ban on the commonly used opioids such as dextropropoxyphene, there may be an increasing abuse of newer opioids such as tapentadol. Here, we report two cases of tapentadol abuse, which to our knowledge are among the first such reported cases from India and discuss its implications in the context of the current opioid scenario in the country.

Case Reports

Case 1

A 27-year-old unmarried male started using codeine cough syrup in late adolescence due to peer pressure and curiosity. Opioid use gradually increased up to 6 bottles/day with craving, tolerance, withdrawal symptoms, loss of control, and early morning use within initial 2–3 years. Due to its escalated cost, he shifted to dextropropoxyphene capsule use – this gradually increased up to 20–24/day within the next 3 years. After dextropropoxyphene ban, he started using tablet tapentadol on advice of a local pharmacist. He would consume up to 300 mg of tapentadol twice or thrice daily along with nitrazepam 10 mg twice daily to enhance the experience. He would often substitute tapentadol with oral tramadol (50 mg) amounting to 24 tablets/day – such excess dosage on two occasions had led to generalized tonic–clonic seizures. In view of the longstanding history of opioid use (total 8 years), involvement in antisocial activities for the procurement of substances, high persistent craving, and lack of any abstinence attempts, buprenorphine maintenance treatment was initiated. At 3-month follow-up, he reported abstinence from opioids with only one lapse in between.

Case 2

A 31-year-old married male with impulsive traits premorbidly and family history of alcohol dependence syndrome in father started taking alcohol and cannabis in late adolescence. He started using buprenorphine for experimentation under peer influence by intravenous route from 19 years of age with an average of 1.2–2.4 mg/day with craving, salience, tolerance, and withdrawal symptoms. The patient used it for 3 years and thereafter was forced to abstain due to nonavailability. He started using tapentadol upon the suggestion of a friend at the age of 30 years to overcome withdrawals of buprenorphine. He would crush 10–20 tablets of 50 mg/day (500–1000 mg), mix it with distilled water, and use it by intravenous route. The tablets were insoluble in water, and he often injected the incompletely dissolved solution. He developed cellulitis of both his arms and multiple scars as he would also inject the same intradermally. He reports that he did not like tapentadol when compared with buprenorphine owing to its tedious methods of use and short duration of action; however, the reasonable price and ease of availability made it preferable. He reports significant withdrawal symptoms related to tapentadol such as nausea, vomiting, chills, goose bumps, running nose, joint pains, and restlessness which would set in after 12 h of last use and lead to further use. Owing to the long duration of use, past failure of antagonist maintenance, and significant harms incurred, he was started on buprenorphine maintenance therapy along with psychosocial interventions.

Discussion

These cases demonstrate the changing pattern of pharmaceutical opioid abuse – the shift from opioids such as codeine, dextropropoxyphene, buprenorphine to tramadol and finally to tapentadol. This transition is mediated both by subjective effects of these drugs and also cost, availability. The second case is particularly important because tapentadol has been used intravenously, and there are reported cases of fatality after such usage. Although such reported cases are rare, it is of immense public health importance given the sizeable number of injection drug users in India.

Due to its prominent μ-opioid receptor agonistic effects, the mood alterations and the euphoria associated lead to its abuse potential albeit less than other potent opioids. In both mouse and rat models, tapentadol has been shown to have physical dependence though less than that of morphine at equianalgesic doses. As per postmarketing surveys, tapentadol is known to have abuse potential to a limited extent only – it may be because of the fact that it has been marketed since 2008 only and systematic data are not available. A recent study reported that though the population-based rates of diversion in the United States are rare – 0.003 for the immediate release and 0.001 for the extended release per 100,000 population, its low cost poses a higher risk.[3] Hence, a recent WHO Expert Committee report emphasizes upon the need for its proper scheduling to avoid abuse. In most of the western countries, it has been classified as a scheduled drug with other opioids such as codeine and morphine.[4] For example, in the USA, it has been classified in schedule II (available for currently acceptable treatment but with severe restrictions) and a similar category in the United Kingdom. However, the picture in India is quite different, and there are only minimum restrictions – not even inclusion in H1 schedule unlike other common prescription opioids and benzodiazepines.

Opioid use is a growing problem in India because of its geographical proximity to the golden crescent and golden triangle, porous borders, inappropriate narcotic control laws, and weak enforcement agencies. India has historically been an opioid producer with socioculturally accepted use. However, in sharp contrast to the social and cultural aspirations of the Indian masses, the Narcotic Drugs and Psychotropic Substances Act, 1985, imposed strict restrictions on the use of traditional opioids leading to the export of most of the opium produced. This led to a severe opioid scarcity in the country, so much so that only 4% of its population with cancer pain was receiving morphine. This also led to the emergence of a teeming population of prescription drug users of low-potency opioids such as buprenorphine, pentazocine, codeine, and dextropropoxyphene which would often be injected. An indirect impact was the rapid increase of injection drug users and HIV among this population. The ban on the opioid analgesic dextropropoxyphene, a WHO ladder of three analgesic drugs and a cheap opioid for pain relief in a poor country like India, has been highly controversial. At present, in India, there is recommendation for the use of tapentadol for few days only in acute pain conditions.[5] In a welcome move, the Ministry of Health and Family Welfare has banned fixed-dose combination of tapentadol and paracetamol since March 2016. However, these case reports highlight that more needs to be done both in terms of pharmacoepidemiology and drug control measures such as urgent inclusion of tapentadol in H1 schedule of the Drugs and Cosmetic Rules, 1945, to guard against the oncoming Trojan horses of the prescription drug epidemic.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.