Alprazolam & Doxepin – A Menacing Masquerade

Introduction

As the most commonly prescribed benzodiazepine, Alprazolam – colloquially known as Xanax, is not a stranger to the pharmacotherapeutic scene. In 2013, a staggering 48 million prescriptions of Alprazolam were made in the United States alone. Despite being known for severe withdrawal symptoms compared to drugs from the same class (e.g. Clozanepam – Klonopin, Diazepam – Valium and Lorazepam – Ativan), Alprazolam is the 2nd most prescribed medication prescribed in emergency department visits [1].

The main indication for Alprazolam is that of anxiety and panic disorders. The Food and Drug Administration (FDA) approved Alprazolam for these indications after 2 large randomized clinical trials in the late 1980s showed its short-term efficacy and tolerability versus placebo. Aside from its positive effects, Alprazolam also exhibits side-effects, which are dependent on dose, frequency of usage, and many other individual factors. According to G. W. Dawson et al, the following table describes Alprazolam’s side effects in comparison to placebo:

Compared to other benzodiazepines, Alprazolam is has a higher potential for misuse, especially in people that have a previous history of problematic consumption with other substances [1]. This may be due, in part, to a series of pharmacokinetic properties that are unique to Alprazolam: – rapid absorption, a short half-life, low lipophilicity (not very fat-soluble). Because of these, Alprazolam comes on quickly, is quite potent, and does not stay in the body for very long, meaning that withdrawal symptoms can occur after a relatively short period of use.

Alprazolam Withdrawal Syndrome

In theory, Alprazolam carries the same general risk of withdrawal as other benzodiazepines. However, because of the characteristics discussed above, the frequency and severity of withdrawal symptoms as a consequence of abruptly stopping Alprazolam usage seems to be higher than with other benzos. Particularly, it seems to be more prone to causing “rebound anxiety” [2]. One study noted that, of 17 patients with underlying panic disorder that stopped taking alprazolam, 15 patients had a relapse or increase in panic attacks, even after a month-long taper [3]. This makes it clear that special care should be taken by doctors that prescribe Alprazolam; although it is useful for treating anxiety and other symptoms quickly and short-term, long term use can create a dependence quicker than other benzos, and stopping the medication, even with a taper, is particularly difficult.

The Masquerade

Despite its sometimes-problemating withdrawal symptoms, Alprazolam is still a gold-standard for the short-term treatment of anxiety and panic disorders. Beyond that, its fast onset of effects, high potency, and higher potential for misuse (code in the medical field for recreational potential), means that Alprazolam is the most popular benzo in the black market. “Xanax” bars are one of the most counterfeit medications in the world, and despite not actually being manufactured by Pfizer, they do usually contain alprazolam. In the past, people had to be careful with dosage, because instead of Pfizer’s 2 mg dose per bar, counterfeits contained anywhere from 1 to 4 mg of alprazolam. However, recent reports have brought attention to Doxepin being circulated under the guise of Alprazolam [6].

Doxepin is a sedating tricyclic drug which is indicated for the treatment of chronic insomnia. A recent systematic review concluded that Doxepin is safe and effective in improving sleep in insomniacs, with mild side effects such as headache and somnolence [4]. However, other side effects such as dry mouth (xerostomia), constipation as well as drowsiness have been reported. Importantly, postural hypotension is a well-recognised adverse effect of Doxepin. Postural hypotension is characterised by a transient depression in blood pressure when one assumes a standing position from a sitting or recumbent one. This can result in a loss of cerebral perfusion – leading to giddiness, light-headedness and loss of consciousness. In other words, what is commonly referred to as being lightheaded and passing out after standing up.

What are the implications of taking Doxepin which masquerades as Alprazolam? In light of the serious withdrawal symptoms of Alprazolam, people who regularly take Alprazolam and unkowingly acquire counterfeits that only contain Doxepin are doubly at risk. On one hand, the individual will likely experience Alprazolam withdrawal symptoms, which in severe cases can cause seizures and other dangerous conditions. On the other, said individual may also suffer the adverse effects of drowsiness, an inability to stay awake during hazardous situations (e.g. driving, or high-risk work such as tractor or crane operation amongst others) as well as postural hypotension [5]. The consequences can be disastrous to say the least, as they not only affect the individual in question, but potentially  also those surrounding him/her. Additionally, Doxepin is acutely toxic in high doses, and is a even sometimes a drug of choice for those attempting suicide [7].

Dark net Alprazolam results reported by the DNSTARS project has shown dose strengths of 2-10x of that advertised [8]. Apparently, dark net vendors have neither the time, expertise nor the equipment to ensure appropriate dosing (or even the presence of the right compound) when pressing pills for consumption. The use of Doxepin as a substitute for Alprazolam should be strongly rejected by end users, and better alerting procedures should be developed within a multi-agency framework that can better reach those who are at most risk.

Feedback from an end user on Reddit, May 2019.

Monitoring this trend is a priority of the DNSTARS project who, together with Energy Control Internationals’ expertise and assistance, continue to innovate in practical harm reduction for end users globally. Special thanks our community member TidyBoy who helped shape the broad response back in February.

References

  1. Ait-Daoud, N., et al., A Review of Alprazolam Use, Misuse, and Withdrawal. Journal of addiction medicine, 2018. 12(1): p. 4-10.
  2. Risse, S.C., et al., Severe withdrawal symptoms after discontinuation of alprazolam in eight patients with combat-induced posttraumatic stress disorder. J Clin Psychiatry, 1990. 51(5): p. 206-9.
  3. Fyer, A.J., et al., Discontinuation of alprazolam treatment in panic patients. Am J Psychiatry, 1987. 144(3): p. 303-8.
  4. Yeung, W.-F., et al., Doxepin for insomnia: A systematic review of randomized placebo-controlled trials. Sleep Medicine Reviews, 2015. 19: p. 75-83.
  5. Pinder, R.M., et al., Doxepin up-to-date: a review of its pharmacological properties and therapeutic efficacy with particular reference to depression. Drugs, 1977. 13(3): p. 161-218.
  6. DoctorX, ALERT: Update on adulterated samples of ALPRAZOLAM, EC Alerts Page, https://energycontrol-international.org/alert-update-on-adulterated-samples-of-alprazolam/ Accessed 2019
  7. Nicole C. White, et al., Suicidal Antidepressant Overdoses: A Comparative Analysis by Antidepressant Type, Journal of Medical Toxicology, 2008, 4(4):p.240.
  8. DNSTARS, Aggregated results data, 2018 “Alprazolam substances”, https://dnstars.vip/results/. Accessed 2019

 

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