Badanie objawów klinicznych, wyników badań paraklinicznych i wyników leczenia u irańskich pacjentów z zatruciem tramadolem: 10-letnie badanie retrospektywne

■ INTRODUCTION

Tramadol, which is a synthetic analgesic medi­cation, has both opioid and non-opioid mechanisms of action; it binds to μ-opioid, noradrenergic and serotonergic receptors to influence pain processing in the central nervous system (CNS) [1, 2]. Initially synthesised by Grünenthal in 1962 and subsequently marketed in Germany in 1977, tramadol was initially introduced in Iran in 1999 as a prescription-only medication with weak opioid activity [3-5]. Although tramadol has a controlled status, it is readily available in Iranian pharmacies and, as a consequence, it has been abused, especially by young people [6-8]. Its side effects are nausea, vomiting and sedation though overdoses may result in serious complications like seizures, respiratory depression, tachycardia, serotonin toxi­city and coma [5, 9-11]. In Iran, tramadol abuse has become a major public health concern, although recent extensive data is scarce compared to previous reports from 2005-2008 [8, 12-15].
The present study tries to shed more light on the clinical symptoms, paraclinical results and consequences of tramadol poisoning in Yazd, Iran over the last 10 years (2014-2023). By contrasting findings with previous Iranian studies, it seeks to identify shifting trends, establish the burden of tramadol abuse and inform targeted prevention strategies.

■ MATERIAL AND METHODS

Ethical approval

This retrospective cross-sectional study was approved by the Ethics Committee of Islamic Azad University, Yazd Branch (IR.IAU.YAZD.REC.1403.009). The patients’ proper consent was obtained, and strict measures were taken to ensure the confidentiality of all information.

Research participants and setting

The research involved patients who were diagnosed with tramadol toxicity and visited the emergency department or were admitted to either the poison control unit or the intensive care units of Shah Vali and Shahid Beheshti hospitals in Yazd, Iran between 2014 and 2023. Incomplete medical files in relation to specific analyses, poisoning due to agents other than tramadol (unless tramadol was the principal agent) and seizures secondary to neurological or metabolic diseases were the exclusion criteria. To reduce selection bias, patients with incomplete records were excluded only from analyses that required the use of missing data. The causes of incomplete records (e.g., cleri­cal errors) were examined to ascertain that there was no systematic bias between patient subgroups or study centres.

Data collection

Data were collected from clinical files and the hospital computer system, including demographic information (age, sex, marital status, edu­cation), history of any addiction (including opioids, illicit drugs, or alcohol) and mental disorder history, hospitalisation data, reasons for tramadol use (as abuse, suicidal attempt, or accident), clini­cal presentation, treatments, paraclinical results (including pH, pCO2, HCO3, CPK, blood glucose, urea, creatinine) and outcomes (including rhabdomyolysis, acute renal failure, death). Polypharmacy was the co-administration of tramadol with other medications, including illicit drugs or prescription medications. Rhabdomyolysis was a specific condition of interest for comparative analysis due to its known association with severe tramadol toxicity and its potential for life-threatening complications like acute kidney injury, despite its lower frequency compared to other symptoms [16]. Rhabdomyolysis was confirmed based on CPK > 975 IU/l as per traditional diagnostic criteria in the literature [12].

Quantitative analysis

Data was analysed using SPSS version 23 (IBM Corp., Chicago, IL, USA). Quantitative variables were presented as medians with interquartile ranges (IQRs) due to non-Gaussian distributions, while qualitative variables were presented as frequencies and percentages. The c2 test made between-group comparisons. A p-value of < 0.05 was regarded as significant.

■ RESULTS

A total of 390 patients with tramadol poisoning from 2014 to 2023 were included in this study. The median age was 26 years (IQR: 20-36), and 68.2% (n = 266) were male, while 53.3% (n = 208) were unmarried. The level of education indicated 34.1% (n = 133) with elementary school, middle school and high school, and 20.0% (n = 78) with high school diploma and higher education, 45.9% (n = 179) had missing data. History of addiction was reported in 24.1% (n = 94) and mental disorder in 30.3% (n = 118). Tramadol abuse was the primary reason for poisoning (73.0%, n = 285), followed by suicide attempt (22.0%, n = 86) and accidental ingestion (4.6%, n = 18). Most patients (76.4%, n = 298) were managed in the poison control unit and 23.6% (n = 91) required intensive care unit (ICU). Hospital length of stay was one day for 63.0% (n = 246), two days for 24.0% (n = 95) and three days for 6.0% (n = 25) (Table I).
Clinical presentation included bradypnea in 26.2% (n = 102), seizures in 23.1% (n = 90; 18.5% simple tonic-clonic, 4.6% status epilepticus) and tachycardia in 19.0% (n = 74) patients. Aspiration pneumonia was present in 11.8% (n = 46) and acute respiratory distress syndrome (ARDS) in 0.3% (n = 1). Paraclinical examination showed increased pCO2 in 11.0% (n = 43), decreased pH in 12.1% (n = 47) and decreased HCO3 in 8.5% (n = 33), indicating respiratory acidosis in some cases. Rhabdomyo­lysis (CPK > 975 IU/l) occurred in 3.1% (n = 12), renal failure in 2.6% (n = 10), and hyperglycemia in 7.2% (n = 28) patients. Treatments included naloxone in 32.1% (n = 125), diazepam in 26.2% (n = 102) and intubation in 4.9% (n = 19). Polypharmacy was present in 20.8% (n = 81). Death occurred in 0.5% (n = 2) of patients (Table I).
Comparative analysis by age group showed that tramadol abuse was more frequent in patients ≤ 25 years (75.7%) compared to those > 25 years (70.5%, p = 0.019), while addiction history was more prevalent in older patients (36.6% vs. 13.0%, p < 0.001) (Table II).
By gender, females had a higher prevalence of tramadol abuse (83.9% vs. 68.3%, p < 0.001), while males reported higher addiction history (32.7% vs. 5.6%, p < 0.001). Rhabdomyolysis prevalence did not differ significantly by gender (p = 0.45) (Table III).
Rhabdomyolysis was significantly associated with seizures (p < 0.001), aspiration pneumonia (p < 0.001) and intubation (p < 0.001) though not with age (p = 0.828) (Table IV).

■ DISCUSSION

This study examines tramadol poisoning in Yazd, Iran from 2014 to 2023. It updates information from earlier studies conducted between 2005 and 2008 and builds upon recent Iranian research [17-20]. The average age of 26 years aligns with earlier reports, which showed average ages ranging from 22.8 to 24.13 [4, 5, 20]. This indicates that tramadol poisoning typically affects young adults, probably because they take risks and do not know much about its dangers. The predominance of males (68.2%) is in line with findings of 73.5-90% male patients [4, 5, 11, 17, 20, 21] and may be related to greater use of substances and social stress in men. Lower educational level (63.0% of patients with known educational status had less than a high school diploma) and a high proportion of unmarried patients (53.3%) support findings linking tramadol abuse with socioeconomic and psychological determinants [20, 22].
Tramadol dependence was the most common cause of poisoning (73.0%), which is in line with Ahmadimanesh et al. (58.3%) research results [5]. However, Majidi et al. [22] reported a higher incidence of suicidal intent (78.9%), possibly because of different study populations or methods. Respiratory depression (26.2%) and seizures (23.1%) were common, which is in agreement with incidences of 18-46.2% in other studies [4, 17, 20]. Respiratory acidosis with an elevated pCO2 (11.0%) underscores the importance of closely monitoring respiratory function, as noted by Rahimi et al. [23]. Rhabdomyolysis (3.1%) was less common than reported by Faraji et al. (6.1%) [24] which is likely due to the more rigorous diagnostic criteria (CPK > 975 IU/l). The low mortality rate (0.5%) aligns with rates ranging from 0 to 1.1% [16, 17, 21] and reflects successful management in most cases.
Our finding that 20.8% of patients had polypharmacy is a critical clinical observation. While tramadol overdose on its own has a low mortality rate, co-ingestion with other CNS depressants like benzodiazepines can significantly increase toxicity and lead to severe outcomes, including respiratory depression, coma and death [25]. Clinical data indicates that overdose death rates can be 10 times higher for patients co-dispensed opioids and benzodiazepines compared to those dispensed opioids alone [6, 26]. This highlights that clinicians need to be vigilant about patients with tramadol poisoning, as they are at risk of polypharmacy, which can profoundly alter the clinical course and increase the risk of adverse outcomes [27-29].
While our study reports on a specific cohort of 390 patients over a decade, it is important to contextualise these findings within the broader public health landscape in Iran. Previous studies have reported a high prevalence of tramadol abuse among specific populations like university students, with rates ranging from 5% to 12.5% in different regions of Iran [2, 30]. Furthermore, a report from the Iran Drug Control Agency has cited a tramadol abuse rate of 26.5% in the gene­ral population [1]. These findings, coupled with the high rate of poisoning due to abuse (73.0%) in our cohort, collectively underscore that tramadol poisoning is a significant and escalating public health concern in Iran, necessitating targeted interventions beyond the medical management of acute cases.
This study is unique in that it analyses data for the last 10 years, with new information on tramadol abuse in Iran. It is distinct from other studies in that it investigates the relationship between rhabdomyolysis and certain illness complications like seizures [31], aspiration pneumonia and intubation [32-36], using comparative analysis (c2 test) to report meaningful associations. The results highlight the need for specific interventions, like public health campaigns, to educate young adults and limit access to tramadol to stop its abuse. We found the significant associations between rhabdomyolysis and seizures, aspiration pneumonia and intubation. While these associations may be considered expected, our findings confirm their presence in a large cohort of tramadol-poisoned patients. Rhabdomyolysis is a well-documented complication of severe seizures, particularly tonic-clonic seizures due to extreme muscular activity that causes direct muscle cell injury and subsequent leakage of myoglobin and other sarcoplasmic proteins into the bloodstream [32, 36]. The presence of rhabdomyolysis is often a marker for the severity of poisoning and the need for intensive care as it is a known risk factor for acute kidney injury [4, 37]. The associa­tions with aspiration pneumonia and intubation further underscore that rhabdomyolysis is part of a complex, multi-systemic clinical picture in the most severely intoxicated patients.

■ CONCLUSIONS

Our 10-year retrospective study of tramadol poisoning in Yazd, Iran, highlights a patient cohort characterised by young, predominantly male individuals. This population frequently presents with severe clinical complications, particularly seizures and respiratory depression, underscoring the severity of these intoxications. The low observed mortality rate, in line with prior reports, demonstrates the effectiv Iran J Toxicol eness of current clinical management in these hospital settings. Our findings underscore the critical need for continuous vigilance, enhanced public-awareness campaigns to deter tramadol abuse and stricter control over its prescription and availability to mitigate this ongoing public health challenge.

Conflict of interest/Konflikt interesów

None declared./Nie występuje. 

Financial support/Finansowanie

None declared./Nie zadeklarowano. 

Ethics/Etyka

This descriptive, cross-sectional, and retrospective study received ethical approval from the Ethics Committee of Islamic Azad University, Yazd Branch (IR.IAU.YAZD.REC.1403.009). Written informed consent was received of patients. Furthermore, strict confidentiality was maintained for all patient information.
The work described in this article has been carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) on medical research involving human subjects, Uniform Requirements for manuscripts submitted to biomedical journals and the ethical principles defined in the Farmington Consensus of 1997.
Treści przedstawione w pracy są zgodne z zasadami Deklaracji Helsińskiej odnoszącymi się do badań z udziałem ludzi, ujednoliconymi wymaganiami dla czasopism biomedycznych oraz z zasadami etycznymi określonymi w Porozumieniu z Farmington w 1997 roku.

References/Piśmiennictwo