1 Theoretical background

The recent increase in the number of migrants seeking refuge in the European Union can be attributed to several political, humanitarian, economic and environmental factors. Leaving one’s home country and adapting to a new environment can be accompanied by various stressors and challenges that can affect physical and mental health, including the loss of family and social support, traumatic experiences, unemployment, poverty, language barriers, cultural adjustment, and discrimination. Research suggests that these circumstances make this population more vulnerable to substance use disorders (SUD), which can be used as a coping mechanism to deal with stress, trauma, and adversity [1]. However, the findings regarding substance use disorders among migrants and refugees are not consistent across all studies. In the last decades, several case reports worldwide have highlighted the addictive potential of pregabalin. A recent systematic review showed that euphoria is a frequent side effect in patients treated with pregabalin [2]. The migrant population and people with other current or past substance use disorders appear to be vulnerable groups for pregabalin use disorder. A 10 year retrospective study published in 2023, which analyzed data on gabapentinoid-related attendances to the National Poison Control Center of Serbia, showed a steady increase in rates of pregabalin abuse, with more than half of the patients who abused pregabalin belonging to the migrant population [3]. Pregabalin is an analogue of the neurotransmitter gamma-aminobutyric acid (GABA) commonly prescribed for diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, neuropathic pain, partial seizures and anxiety disorders. The authors aim to present two cases of pregabalin use disorder documented in the Unidade Habitacional de Santo António (UHSA), a temporary detention center for undocumented migrants, in Porto. According to the definition provided by the International Organization for Migration, an undocumented or irregular migrant is an individual who lacks legal status in a transit or host country due to unauthorized entry, violation of entry conditions, or the expiration of their visa or work permit [4]. The authors work as medical doctors at Doctors of the World (DW), a non-governmental organization of humanitarian aid and development cooperation that collaborates with UHSA to provide access to essential medical care to undocumented migrants who, while awaiting resolution of their legal process, have limited access to public health care. Although pregabalin is an uncommon recreational drug in Portugal, these case reports are relevant to alert to its greater popularity among the migrant population and the risks of abuse.

2 Methods

2.1 Study design

These case reports were conducted at the Unidade Habitacional de Santo António (UHSA), a temporary detention center for undocumented migrants subject to a measure of removal from Portuguese territory carried out by competent authorities. UHSA can accommodate up to 30 people. During this period undocumented migrants have access to several services, including social, legal, religious and medical support.

2.2 Participant selection and data collection

Two distinct cases of pregabalin use disorder were identified and thoroughly documented. Detailed information regarding the cases was gathered through a clinical interview. The diagnostic criteria for pregabalin use disorder were based on established guidelines, including the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR).

3 Case presentation

3.1 Case report 1

A 25-year-old man, born in Morocco, left his country in 2012 and temporarily resided in several countries, including Belgium, Germany, France, and Spain. Upon his arrival in Portugal in 2021, he was admitted to the psychiatric inpatient department due to homelessness, disorganized speech and behavior. Abuse of clonazepam and pregabalin (approximately 900 mg a day) was detected, and these drugs were slowly discontinued. The patient had a history of prior hospitalizations in France for alcohol, cannabis and cocaine use disorders accompanied by psychotic symptoms. After achieving clinical stabilization, the patient was discharged to UHSA as an undocumented migrant. At UHSA, the patient sought for assessment by DW due to anxiety symptoms, psychomotor restlessness and insomnia. He persistently requested an increase in the dose of pregabalin he had previously been taking (a supratherapeutic dose), stating that he needed high doses to feel the desired effect. He claimed a prescribed origin but acknowledged an independent escalation, reporting euphoria, enhanced well-being and reduced anxiety with high doses. During the assessment he was tense and restless. His cooperation was limited and his speech was characterized by preseveration on the need for increased pregabalin dose. He also complained with chills and nonspecific somatic pain. He displayed resistance and anger towards the medical team’s suggestions. The patient was diagnosed with a moderate pregabalin use disorder, fulfilling at least 4 criteria according to DSM V TR: taking the substance in larger amounts (criteria 1), craving or urges to use the substance (criteria 4) developing tolerance (criteria 10) and developing withdrawal (criteria11).

3.2 Case report 2

A 35-year-old man from Tunisia arrived in Portugal in 2020. He was temporarily in other European countries without legal documentation and was previously arrested in France for substance-related activities. Regarding his psychiatric history, he had a history of alcohol, cannabis and opioid use disorder and was currently in early remission. He also had a history of self-injurious behavior and impulsive behavior. The patient was apprehended to UHSA due to his lack of legal status in Portugal and, a few days later, he was assessed by DW for his complaints of insomnia, tremor and anxiety. During the evaluation, the patient exhibited irritability and restlessness. He had multiple scars along his arms consistent with self-inflicted cuts. His speech was rapid and pressured and he persistently demanded an increase in the dose of pregabalin, a medication he had previously been taking at doses of 1000 mg per day. He reported using pregabalin to cope with his anxiety and intrusive thoughts from traumatic memories. When questioned, he vaguely mentioned several adverse events during his life, including the death of close family members and exposure to violent environments, but he remained uncooperative in exploring his symptoms and focused his speech on the need to obtain pregabalin. He confirmed self-administration of pregabalin and dose escalation without medical supervision. He reported periods of cravings that led to drug-seeking behavior. The patient was diagnosed with a moderate pregabalin use disorder, fulfilling at least 4 criteria according to DSM V TR: taking the substance in larger amounts (criteria 1), craving or urges to use the substance (criteria 4) developing tolerance (criteria 10) and developing withdrawal (criteria11). A comorbid stress and trauma related disorder was also suspected, specifically Post Traumatic Stress Disorder (PTSD), with subsequent assessments needed to specify the latter diagnosis.

4 Discussion

A growing body of research suggests an increasing global trend towards the inappropriate use linked with gabapentinoid medications, particularly pregabalin. When it was first approved in 2004, pregabalin was placed by the Food and Drug Administration (FDA) on Schedule V of the Controlled Substances Act due to its abuse potential [5]. Several clinical and epidemiological studies have shown that pregabalin use disorder occurs particularly in patients with other current or previous substance use disorders. In a study of methadone users, in which a questionnaire was used to screen for other substance use, 3% and 19% of patients used pregabalin and gabapentin without a prescription, respectively, and these patients stated that they used these substances to get high (76%) or to enhance the effect of methadone (38%) [6] Recently, a multisource investigation of data collected through the French addictovigilance system, from 2010 to 2019, showed an intensification of gabapentinoid abuse over the years. During this period, 258 individuals were reported with pregabalin abuse (versus 7 individuals with gabapentin abuse), and the proportion of falsified prescriptions with pregabalin increased sharply from 2018 (below 3.0% up to 2017 and increased to 11.9% in 2018 and 23.8% in 2019) [7].

In accordance with prior research, our case reports align with a 2021 systematic review on gabapentinoid addiction, which identified 19 cases of pregabalin abuse, with 16 having tolerance and withdrawal symptoms. Notably, the majority of these cases, akin to our findings, exhibited a background of addiction to conventional psychoactive substances, primarily alcohol, benzodiazepines, and opioids. Compared to gabapentin, pregabalin use was more frequently associated with behavioral dependence symptoms and with a transition from prescribed therapeutic doses to self-administration, which resonates with the trajectory observed in our two patients [8]. Regarding our second case report, the patient used pregabalin to manage anxiety and intrusive memories, which led us to consider the presence of a comorbid PTSD. The comorbidity PTSD-SUDs is well documented and a recent case report published in 2020 shared a case of a migrant diagnosed with a PTSD and a comorbid pregabalin use disorder, reflecting on the role of migration journey as a potential mediator between PTSD and PUD [9]. Both of our cases have a history of an extensive migratory journey, transiting multiple countries, which puts them at greater risk of the challenges documented at this stage of the migratory process, namely the risk of increased exposure to violence, detention, lack of access to basic services (such as medical care) and social precariousness. Psychological trauma can have a significant influence on substance use disorder. Substance use can initially seem to relieve distress through pleasurable sensations or avoidance of negative emotions that may follow stressful experiences.

In recent years, the general press has reported on the excessive use of pregabalin in refugee camps, without prescription or supervision, revealing the existence of a growing black market. Another study in France investigated the recreational use of pregabalin among adolescents and showed that 81% of the users were homeless or living in migrant shelters [10]. These data suggest that not only people with a history of substance abuse, but also the migrant population is particularly vulnerable to pregabalin use disorders and that it becomes relevant to screen the consumption of this substance in these populations.

Although pregabalin is generally well tolerated, euphoria emerges as a dose dependent adverse effect, accompanied by reported improvements in socialization ability and a heightened sense of relaxation. In higher doses, sedative, psychedelic and dissociative effects are also reported. The presence of a euphoric mood may contribute to pregabalin abuse and this can be elucidated by examining its pharmacodynamic and pharmacokinetic characteristics. Pregabalin is a six-fold more potent inhibitor of the α2δ subunits containing voltage dependent calcium channels than gabapentin. Also, it is absorbed more rapidly, taking one hour to reach the maximum plasma level compared to three to four hours with gabapentin, and it has higher bioavailability [2].

Certain signs should alert health professionals to the presence of a pregabalin use disorder, such as the development of tolerance, requests for dose increase, and drug-seeking behavior. Prescribers should also be careful dealing with patients who directly request for pregabalin. If prescribed, pregabalin treatment should be reviewed regularly, and if it is necessary to increase the dose, this should be done slowly. The same applies to the gradual reduction of pregabalin to avoid discontinuation syndrome. A previous study conducted at UHSA showed a high prevalence of mental health disorders among undocumented migrants, with mental disorders due to psychoactive substances being the second most prevalent [11]. This reality highlights the importance of implementing prevention programs targeted at this population and the need for a multidimensional mental health care approach with diagnostic and treatment resources in detention centers. Furthermore, there is a need to increase multicultural competencies of Portuguese clinicians when working with migrants and ethnic minorities to effectively build healthcare interventions. Components of cultural competence include awareness of other’s background, experiences, stereotypes and preconceived notions, knowledge about the groups one works or interacts with and skills in cultural aspects of assessment and intervention.

4.1 Limitations of this study

This study had some major limitations, which included the lack of patients' previous medical records, the lack of cooperation in assessing psychiatric and personal history, as well as a more accurate history of current and past substance use, and the absence of family members to corroborate the patients' information.

5 Conclusion

Pregabalin, an anticonvulsive drug used to treat several medical conditions, can induce euphoria in some patients and have addictive characteristics that can easily be overlooked. In recent years, there has been a significant increase in recreational use, especially among the migrant population. Physicians and pharmacists must be cautious when working with high-risk populations, particularly migrants with a history of other substance use disorders. Harm reduction programs and interventions targeting the most prevalent mental health problems among the migrant population are needed, while acknowledging the social and ecological context of this population.