Assessment of treatment efficacy for codeine-containing cough syrup dependence using single-photon emission computed tomography

Introduction

Codeine, an alkaloid derived from poppy straw or latex from seed pods, has been widely used as an antitussive agent for many years (1). It is one of the most commonly misused opioids in non-medical settings (2). Codeine-containing cough syrup (CCS) are frequently used to relieve cough and are easily accessible without the need of a prescription. Although short-term or occasional use of CCS typically does not result in dependence, prolonged or continuous use can result in both physical and psychological dependence (3). The misuse of CCS has become increasingly prevalent among young people worldwide (4).

In recent years, the non-medical use of opioids has risen substantially on a global scale. Despite this trend, limited investigation has been conducted on the treatment needs and characteristics of individuals seeking treatment for opioid dependence (5). The adverse effects of pharmaceutical opioid misuse have emerged as a significant global health concern (6-8). Given the differences between codeine users and those dependent on stronger opioids—such as heroin—in terms of clinical presentation, treatment needs, and socio-demographic factors (e.g., employment and education status) (9,10), it is essential to develop tailored treatment strategies for individuals with codeine dependence.

Neuro-imaging studies have identified various brain abnormalities in patients with neurological and psychiatric disorders. These techniques provide valuable insights into brain changes in patients with CCS dependence (11). Molecular imaging methods, such as single-photon emission computed tomography (SPECT), offer distinct advantages over planar imaging modalities. In addition to detecting structural abnormalities, SPECT can monitor functional changes in the brain before and after treatment interventions, thereby facilitating a more comprehensive evaluation of treatment efficacy (12). Furthermore, the evaluation of presynaptic dopaminergic integrity has emerged as a crucial objective in substance dependence research. Codeine, as an opioid, exerts its rewarding and addictive effects primarily through the activation of the mesolimbic dopamine pathway, which originates in the ventral tegmental area and projects to the striatum. Chronic opioid use is known to dysregulate this system, leading to altered dopamine neurotransmission. ^99mTc-TRODAT-1, a cocaine analogue with high affinity and selectivity for the dopamine transporter (DAT)—a key regulator of dopaminergic signaling located on presynaptic terminal—enables in vivo quantification of DAT availability in the striatum using SPECT imaging (13). A reduction in DAT binding has been consistently reported in various substance use disorders, including opioid dependence, and is considered a biomarker of dopaminergic terminal impairment. Therefore, by quantifying striatal DAT availability before and after comprehensive treatment, this study aimed to implement a comprehensive treatment approach for patients with CCS dependence and to assess its effectiveness using SPECT imaging. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-557/rc).

Methods

Participants

Sixty individuals participated in this study. Of these, 31 were healthy volunteers without a history of psychiatric disorders, neurological conditions, or significant medical problems. The remaining 29 participants were patients with CCS dependence, seeking treatment at the hospital. The diagnosis of CCS dependence was established based on the criteria outlined in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from all participants before their inclusion in the study. Ethics approval was granted by the ethics committee of Affiliated Hospital of Guangdong Medical University (No. 2024-6-10). This study started on September 1, 2011 and the patients were enrolled in the study since that time. A strict, pre-defined imaging and analysis protocol was conducted, all participating physicians and technicians received standardized initial and periodic refresher training to minimize inter-operator variability and ensure consistent data acquisition and interpretation over time.

Comprehensive methods

Medication

Detoxification treatment was administered to patients with CCS dependence who sought medical care for the first time. Withdrawal symptom management was prioritized as part of the treatment process. Additionally, therapeutic measures were implemented to address potential brain damage. Individualized treatment method was used for each patient. Naloxone, naltrexone and so on were used as opioid receptor block therapy. Fluoxetine, paroxetine and sertraline were also used for these patients. The big data platform showed that for most the patients with mental disorders, including the CCS dependence, the individualized treatment is important.

Psychotherapy and behavioral therapy

Mental health education was provided to patients to support their adaptation to the social environment. Efforts were made to assist patients in establishing new, healthy behavior patterns. Additionally, patients were encouraged to engage in physical activities such as walking, swimming, and so on.

Follow-up therapy

Patient relapse was monitored through follow-up therapy. During these follow-up sessions, medication management, psychotherapy, and behavioral therapy were adjusted and intensified.

Imaging

A dual-detector SPECT system (Siemens Company, Munich, Germany) was used for imaging, with ^99mTc-TRODAT-1 serving as the imaging agent. The imaging procedure was conducted according to previously described methods (3).

Data acquisition parameters included an amplification factor with a Zoom =1.78, a 360° synchronous rotation, and a 128×128 matrix of the dual probe. Attenuation correction was performed with the Chang method.

Healthy volunteers underwent a single SPECT DAT scan. In contrast, patients with CCS dependence received two scans: one before the initiation of therapy and another after completing at least 6 months of treatment.

Radiopharmaceutical details were as follows: ^99mTc-TRODAT-1, administered at a dose of 25mCi per patients or the healthy volunteer; time interval from injection to scanning, 3 h; single-frame acquisition time, 18 s per frame; total of 128 frames; total scanning time: 38.4 min (noting that with advances in scanner technology, scanning times have been reduced in recent studies). The scanning body area was limited to the head.

The volume (V), weight (W), and uptake ratio of corpus striatum/the whole brain (Ra) were calculated by the pre-installed software of the system. V refers to the functional volume of tracer uptake as defined by the software’s thresholding algorithm, and not the absolute anatomical volume (14). The algorithm of V, W and Ra were as follows:

V=VL+VR=(∑i12Ci⋅S)L+(∑i12Ci⋅S)R[1]

W=WL+WR=1.05VL+1.05VR[2]

Ra=Bn∑i12Wci×100%[3]

Data analysis

The data were presented as mean ± standard deviation (SD). Statistical analysis was conducted using SPSS version 16.0. Differences between groups were assessed using the t-test. For comparing between groups of experimental group vs. control group, the independent samples t-test was used. And for comparison of before-after measurements the paired t-test was used. Before doing the t-tests, the normality of the data was tested by Shapiro-Wilk test.

A P value of less than 0.05 (P<0.05) was considered the threshold for statistical significance in all tests. The data was normally distributed. It was confirmed and the appropriate statistical tests were applied accordingly. Bonferroni correction was used to control the family-wise error rate, resulting in a significance level of P value <0.0055 (0.05/9).

Results

Changing clinical manifestations

Following therapy, clinical symptoms in patients with CCS dependence revealed varying degrees of improvement. Symptoms of physical dependence and cravings either disappeared or were significantly reduced. Anxiety and depression symptoms were notably alleviated. Sexual function demonstrated significant enhancement, and sleep quality improved significantly. Family relationships became more harmonious in many cases. Additionally, some patients obtained stable employment after treatment. A few patients expressed reproductive intentions, with semen analysis results indicating normal parameters. To evaluate the clinical manifestations changing there were scales used to track the improvement in the symptoms (15).

Efficacy evaluation

Visual evaluation analysis

In this study, all 29 patients with CCS dependence were male, with a mean age of 21.60±2.27 years, and all 31 healthy controls were male, with a mean age of 21.73±2.19 years. Before treatment, SPECT DAT imaging revealed varying degrees of abnormality compared to the healthy control group. The corpus striatum appeared smaller and exhibited irregular morphologies, including irregular, thin strip, and dumbbell-shaped structures (Figure 1A). A significant reduction in the quantity and activity of DAT was observed bilaterally in the striatum, accompanied by a significant decrease in both the distribution range and the number of binding sites (Figure 1B, Table 1). These findings were consistent with those reported in previous study (16).

Figure 1 SPECT DAT images in the healthy control group and a patient with CCS dependence before and after treatment. (A) SPECT DAT image of a healthy control. The bilateral striatum was normal (arrows). (B) SPECT DAT image of a patient with CCS dependence before treatment. The bilateral striatum was damaged (arrows). (C) SPECT DAT image of the same patient with CCS dependence after treatment. The bilateral striatum was repaired (arrows). CCS, codeine-containing cough syrup; DAT, dopamine transporter; SPECT, single-photon emission computed tomography.

Following treatment, significant improvements were noted in the SPECT DAT images of the patients. The bilateral striatum regained a shape resembling the typical “panda eyes” configuration observed in the healthy control group. The radioactive distribution became uniform and symmetrical, and the volume of the bilateral striatum increased significantly. Non-specific uptake in the brain and cranial plate imaging revealed a noticeable reduction. Additionally, the quantity and activity of DAT, as well as the distribution range and binding sites, were significantly enhanced (Figure 1C).

Quantitative analysis

The W (22.98±7.62 vs. 35.58±3.64 g), V (21.12±5.65 vs. 35.24±3.31 cm³), and Ra (4.16%±1.12% vs. 7.93%±0.86%) of the bilateral striatum in patients with CCS dependence were significantly reduced compared to the control group before treatment (Table 1). Following treatment, the W (32.44±9.60 vs. 35.58±3.64 g), V (30.90±9.14 vs. 35.24±3.31 cm³), and Ra (7.06%±1.84% vs. 7.93%±0.86%) values in patients with CCS dependence remained significantly lower than those of the control group (Table 2).

However, a comparison between pre- and post-treatment measurements in patients with CCS dependence demonstrated a significant increase in W (22.98±7.62 vs. 32.44±9.60 g), V (21.12±5.65 vs. 30.90±9.14 cm³), and Ra (4.16%±1.12% vs. 7.06%±1.84%) values after treatment (Table 3).

Discussion

CCS are medically valuable drugs that, when prescribed and used appropriately, can effectively treat coughs. However, in recent years, the non-medical use of CCS has increased significantly across many countries. Although codeine is considered less addictive than other opioids, research on effective treatment strategies for CCS dependence remains limited. Previous studies that explored new treatment approaches for codeine dependence did not achieve favorable outcomes. Recently studies have highlighted the need for more precise guidelines and consideration of regulatory changes, such as reclassifying codeine-containing medicines to prescription-only status, to support pharmacists in mitigating risks associated with codeine misuse (17,18). Therefore, the development and validation of comprehensive treatment methods for CCS dependence remain necessary.

The identification of objective methods to evaluate treatment efficacy for patients with CCS dependence is critical (19,20). Various assessment scales have been applied to evaluate the effectiveness of treatments for patients with substance use disorders. However, these scales are often influenced by subjective factors, making it difficult to obtain reliable and objective results. In this study, SPECT DAT imaging was used to assess treatment efficacy. This imaging modality provides quantitative data on brain abnormalities and offers an objective assessment of the therapeutic effects in patients with CCS dependence.

SPECT is a nuclear medicine imaging technology widely used for both diagnostic purposes and evaluation of therapeutic interventions. As a functional neuroimaging tool, SPECT has demonstrated the presence of brain abnormalities in a range of neurological and psychiatric disorders (21), including CCS dependence. SPECT offers significant advantages, including the ability to monitor dynamic changes in brain function before and after treatment compared to static imaging techniques. This capability to provide real-time assessment of functional changes represents a key advantage of SPECT in evaluating treatment outcomes.

Of course, some other functional neuroimaging tool, such as positron emission tomography (PET), can also be used in such studies. One PET study found that chronic opioid use induces long-lasting striatum dopamine neuron impairment, and prolonged opioid withdrawal can benefit the recovery of impaired dopamine neurons in the brain in one PET study, in which, (¹¹C)-2beta-carbomethoxy-3beta-aryltropane [(¹¹C) CFT] was used as a brain DAT ligand (22). In another study the reduced DAT availability in heroin-dependent subjects was also be confirmed by the PET study, in which, the 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane (¹⁸F-FECNT) was used as a PET radiotracer (23). However, the price of the PET exam is much more than that of the SPECT.

In this study, ^99mTc-TRODAT-1 was used as the radiotracer. This agent has been widely utilized in SPECT imaging to assess DAT availability, particularly in alcohol and opioid-dependent subjects (24). SPECT DAT imaging provides an objective means of assessing dopaminergic function in presynaptic terminals, which is crucial for the differential diagnosis of conditions associated with striatal dopaminergic deficiency, including both psychiatric and movement disorders. In cases where diagnostic uncertainty exists, SPECT DAT imaging can help in confirming or excluding dopamine-deficient diseases (25). Additionally, it can detect early dopaminergic dysfunction in patients at risk for psychiatric disorders, as reduced radiotracer binding to DATs in the striatum often manifests during the prodromal stage of these conditions. Numerous studies have supported the use of SPECT DAT imaging in diagnosing psychiatric disorders and other conditions, including CCS dependence, with a particular focus on its clinical applications and practical imaging protocols. Semiautomatic quantitative analysis of ^99mTc-TRODAT-1 SPECT using automated three-dimensional volume of interest (VOI) has shown excellent diagnostic performance in many diseases characterized by striatal pathology, including CCS dependence and Parkinson’s disease (26).

CCS dependence, like other forms of substance addiction, is associated with brain damage (27,28). This dependence induces pathological changes, particularly in the bilateral striatum, which can be detected using SPECT imaging. The findings of this study indicate that addressing brain damage is essential in the treatment of CCS dependence. Effective management of these neurological impairments may improve the likelihood of full recovery. For patients experiencing symptomatic relief, SPECT imaging would show significant improvement in brain function. In contrast, patients with partial recovery would show only incomplete improvements. These incomplete improvements are correlate with sustained abstinence, functional recovery, and relapse risk. Greater improvements usually mean the longer sustained abstinence, better functional recovery, and a lower relapse risk, while lesser improvements indicate the opposite.

The comprehensive treatment methods applied to patients with CCS dependence in this study demonstrated effectiveness. Post-therapy, some clinical symptoms resolved, while others indicated significant improvement. Visual assessment of SPECT DAT imaging revealed notable improvements in the images of patients with CCS dependence after therapy compared to pre-treatment images. Similarly, quantitative analysis revealed significant increases in the W, V, and Ra of the bilateral striatum following therapy. These findings provide further evidence supporting the efficacy of the comprehensive treatment methods used in this study.

Furthermore, this study has several limitations that should be considered. First, weight and volume may not have much practical significance. The group differences/treatment effects was also an important factor. In the further study this factor should also be considered. Second, the baseline characterization of participants, particularly regarding detailed socio-economic status, co-morbid psychiatric conditions, and full medical history, was not comprehensively collected. This was a consequence of the study’s initial primary focus on neuroimaging outcomes. The lack of these data limits our ability to fully assess the baseline comparability of groups beyond age and sex, or to analyze potential confounding factors influencing treatment response. Our study cohort consisted exclusively of young male patients. While this reflects the predominant demographic of individuals presenting with CCS dependence at our treatment center, it undoubtedly introduces a selection bias and limits the generalizability of our findings. The pathophysiology of substance dependence, treatment response, and functional brain recovery may be influenced by sex-based biological differences (e.g., hormonal effects on dopamine signaling) and age-related factors. Consequently, our results are most directly applicable to young adult males. Future studies must make a concerted effort to include female participants and a broader age range to determine the universality of our observations and to explore potential demographic modifiers of treatment efficacy.

However, the limited sample size in this study may constrain the generalizability of these conclusions. And the method of taking the striatum/cerebellum ratio is better, which has been widely applied in similar studies in recent years. However, this study started relatively early and lasted for a longer time due to the reasons such as case collection, and so on.

At the beginning of this study, devices such as PET/magnetic resonance (MR) had not yet been widely applied on a large scale. When the research started, there was only the SPECT device could be used. In the subsequent research, devices such as PET/MR may be adopted for this purpose, which would make it convenient to obtain magnetic resonance imaging (MRI) structural data.

Future studies with larger sample sizes are needed to validate these findings. If confirmed, SPECT DAT imaging could become a standard method for evaluating treatment efficacy in CCS dependence. Future research efforts should explore the effectiveness of alternative therapeutic approaches for CCS dependence while continuing to utilize SPECT DAT imaging for objective evaluation.

Previous studies have reported biochemical changes before and after therapy in these patients, which may serve as diagnostic markers. Collectively, findings from this study and earlier research indicate that objective measures, such as neuroimaging, could potentially replace subjective tools like scales and questionnaires in the future.

Conclusions

SPECT imaging seems to be a valuable tool for evaluating treatment effectiveness in patients with CCS dependence. The results of this study indicate that SPECT imaging may offer a reliable diagnostic and therapeutic evaluation criterion for CCS dependence. SPECT imaging can be used for treatment monitoring, prognosis, or therapeutic decision-making in routine clinical care.

Acknowledgments

We would like to acknowledge the hard and dedicated work of the Big Data Platform of Affiliated Hospital of Guangdong Medical University that implemented the intervention and evaluation components of the study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-557/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-557/dss

Funding: This work was supported by the grants from the High-Level Talents Scientific Research Start-Up Funds of the Affiliated Hospital of Guangdong Medical University (No. GCC2021014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-557/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from all participants before their inclusion in the study. Ethics approval was granted by the ethics committee of Affiliated Hospital of Guangdong Medical University (No. 2024-6-10).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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