Stability of Medications Administered via Enteral Feeding Tubes: A Systematic Review

Authors: Lena Alodat, Wejdan Shahin, Lina Breik, Ayman Allahham

Abstract

Feeding tubes are essential for patients unable to maintain adequate oral intake, serving multiple purposes including nutrition delivery and medication administration. The impact of administering medications through feeding tubes on their stability requires systematic investigation. This review aims to systematically evaluate factors affecting medication stability when administered via enteral feeding tubes versus oral administration in healthy populations, focusing on solid dosage forms converted to liquid formulations. A comprehensive search was conducted across PubMed/MEDLINE, Embase, and CINAHL databases from July to October 2024, using a combination of MeSH and non‐MeSH terms. Studies that assessed medication stability in enteral feeding tubes were included, while those that did not report on this outcome were excluded. The risk of bias was evaluated using ROBINS‐I, RoB‐ II, Cochrane tools, and the QUIN tool. From 2368 articles, 115 were retained for further assessment, and finally 24 met the inclusion criteria and were included, comprising 16 in vivo, 4 in vitro, and 4 combined studies. Approximately 20.8% of the studies found reduced stability/bioavailability for certain medications, such as warfarin and tolvaptan, while 8.3% of the studies found enhanced absorption, as observed with clopidogrel. Most medications maintained their stability. This systematic review suggests that enteral feeding tube administration can variably affect medication stability, influenced by factors such as tube material and preparation methods. Although most medications remain stable, concerns regarding instability and quality persist. The findings of this review provide a foundation for developing evidence‐based guidelines to optimize clinical practice and improve patient outcomes.

Study Highlights What is the current knowledge on the topic? ○Administering medications through feeding tubes can affect how well they work, depending on factors such as the drug‘s formulation, the type of tube used and the route and method of administration. Most existing studies provide broad recommendations, but there is limited understanding of how individual drugs behave under these different conditions. What question did this study address? ○This study explored how medications behave when given through feeding tubes in healthy individuals, without the influence of food. The goal was to understand how drugs interact with the feeding tubes, under normal physiological conditions, without interference from illness or diet. What does this study add to our knowledge? ○By focusing on healthy individuals, this review gives a clearer picture of the drug‘s natural stability and how it interacts with feeding tubes. It shows that drug‐specific information is needed, rather than relying on general guidelines and highlights the importance of better education and training for healthcare professionals who prepare and administer these medications. How might this change clinical pharmacology or translational science? ○These findings can support the creation of more precise drug‐specific guidelines for administering medications through feeding tubes. This could improve safety and treatment outcomes for patients. The review also provides a foundation for future pharmacokinetic studies and updates to clinical practice guidelines, helping to translate laboratory findings into safer and more effective care.

Introduction

Enteral feeding tubes play an essential role in providing nutrition to individuals unable to consume food orally due to dysphagia or severe malnutrition [1]. These tubes also facilitate the administration of medications in patients who are unable to swallow solid oral dosage forms [2]. Feeding tubes are typically categorized into short‐term (e.g., nasogastric [NG] tubes) and long‐term (e.g., percutaneous endoscopic gastrostomy [PEG] tubes) [3]. Their use has increased with the growing aging population and improved survival following major trauma [4]. In Australia, it is estimated that between 30% and 50% of aged care residents have difficulties in chewing and swallowing [5], and over 7000 individuals in the community across Australia and New Zealand rely on a feeding tube [6].

Despite the growing use of enteral feeding tubes, there remains limited consolidated information on the stability of medications delivered through this route [2]. Although liquid formulations are preferred, many drugs are only available in solid form and must be modified, typically by crushing and suspending, for administration through the tube [7]. This modification process raises concerns about altered physicochemical properties, reduced efficacy, and potential toxicity [8, 9]. Klang identified several medications, such as amiodarone, calcium carbonate, and clotrimazole, as unsuitable for enteral tube administration. Furthermore, 46 medications, including aluminum hydroxide and cabergoline, were deemed inappropriate for jejunal delivery [10]. The US Food and Drug Administration has not authorized the use of most oral medications via enteral tubes [10]. Klang's study, however, focused on physical administration issues and did not address how drug absorption or pharmacokinetics may change when solid dosage forms are altered [10].

Previous systematic reviews have examined specific aspects of enteral feeding tube practices, such as service delivery improvements in home settings [11], the risks of administering crushed tablets to individuals with swallowing difficulties [7], and medication administration challenges in stroke patients receiving enteral nutrition [2]. Although these reviews provide valuable insights into discrete clinical scenarios, there remains a gap in the literature regarding the broader issue of medication stability—particularly when solid oral dosage forms are modified and delivered as liquids through feeding tubes.

Aim

This review aims to evaluate the physicochemical and pharmacokinetic stability of medications administered via feeding tubes after converting solid oral dosage forms into liquids. The focus is on healthy adult participants to investigate the medications' behavior under ideal physiological conditions, offering a baseline for interpreting drug–tube interactions [12, 13], examining the influence of feeding tube material, tube diameter, and preparation methods. The findings aim to inform best practices for medication administration through feeding tubes and minimize associated risks.

Methods

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (registration CRD42024580820). Only minor adjustments were made to the protocol prior to data analysis.

Search Strategy

Search strategy was employed to identify relevant studies. Searches were conducted across PubMed/MEDLINE, Embase, and CINAHL databases between July and October 2024. The strategy combined Medical Subject Headings (MeSH) and non‐MeSH terms using Boolean operators and truncation, as detailed in Table S1. No restrictions were placed on publication year, but only studies published in English were considered.

Study Selection

Eligible studies included those that assessed the chemical and/or physical stability of a single solid oral medication administered through an enteral feeding tube (e.g., NG, gastrostomy [G], jejunostomy [J]) using water as the only solvent. Both in vitro and in vivo study designs were considered, provided the same dosage form was used in experimental and comparator conditions. Studies involving healthy adult participants, with no co‐administration of food, were included.

Exclusion criteria were review articles, conference abstracts, editorials, brief reports, posters, non‐English publications, studies on liquid formulations, co‐administered medications, pediatric or animal populations, critically ill participants, or those assessing medication stability in the presence of food.

All identified records were uploaded to Covidence for screening. Two independent reviewers (L.B. and L.A.) screened titles and abstracts, resolving any discrepancies through discussion or with a third reviewer (W.S.). Full‐text screening was similarly conducted independently by two reviewers (L.A. and W.S.), with disagreements resolved by consensus or consultation with a third reviewer (A.A.).

Data Extraction

Data extraction was conducted by two independent reviewers (L.A. and W.S.) using a predefined Excel spreadsheet. Extraction captured variables including first author, publication year, country, study design, sample size, main objectives, type and diameter of feeding tube, dosage forms, stability type (physical or chemical), class of medicine used, participants, duration of feeding tube use, measurement instrument, factors affecting stability, stability/bioavailability outcomes, and stability assessment methods. Data accuracy was independently verified by two authors (A.A. and W.S.).

Risk of Bias Assessment

The risk of bias in randomized crossover trials was independently assessed by two reviewers (L.A. and W.S.) using the Cochrane RoB‐II tool, which evaluates key domains including the randomization process, deviations from intended interventions, missing outcome data, outcome measurement, and selection of the reported results [14]. For non‐randomized studies, the ROBINS‐I tool was used to identify potential biases related to confounding, participant selection, classification of interventions, deviations from intended interventions, missing data, outcome measurement, and selective reporting [15]. In vitro studies were assessed using the QUIN tool, which considers factors such as the presence of appropriate comparison groups, clarity and reproducibility of methodology, outcome measurement, and statistical analysis [16]. Studies scoring above 70% on the QUIN tool were considered to have a low risk of bias, scores between 50% and 70% indicated moderate risk, and scores below 50% signified high risk [16]. All studies that were observed were included regardless of their risk of bias assessment. Any discrepancies between reviewers were resolved through discussion.

Results

A total of 2368 records were screened, 115 full‐text articles assessed for eligibility, and 24 studies were included in this review (see Figure 1).

Study Characteristics

The key characteristics of the included studies were summarized (Table 1). Studies were conducted across multiple countries, primarily the United States (n = 16), with others from Germany (n = 3), the United Kingdom (n = 3), Sweden (n = 1), Japan (n = 1), and Austria (n = 1). The designs included 16 in vivo, 4 in vitro, and 4 combined in vivo/in vitro studies. Sample sizes ranged from 9 to 60 participants, mostly adults aged 18–65 years, with five studies enrolling only male participants [20, 22, 31, 32, 37].

The enteral feeding tubes used included NG, G, PEG, and jejunal types (J). Tube sizes ranged from 5 to 24 French (Fr), with variable administration times post‐drug delivery. Analytical techniques varied across studies, including high‐performance liquid chromatography (HPLC) with UV detection, liquid chromatography–mass spectrometry (LC–MS/MS), and UV spectroscopy.

Risk of Bias Within Studies

Most randomized in vivo studies showed some concerns or high risk in domains related to the randomization process and to deviations from intended interventions, largely due to a lack of blinding. Missing outcome data and selective reporting were low or moderate risk across most studies. In vitro studies showed moderate risk of bias, mainly due to incomplete reporting and methodology details (see Table 2 and Figure 2).

Results of Individual Studies and Synthesis of Results

Overall, 70.8% (n = 17/24) of studies found no change in drug stability, 20.8% (n = 5/24) reported decreased bioavailability, and 8.3% (n = 2/24) reported increased absorption. The majority of both the in vivo and in vitro studies reported no change to the stability of the drugs used with the feeding tubes (75%: n = 15/20 for in vivo and n = 6/8 for in vitro) (Table 3).

Factors Affecting Medications Stability/Bioavailability

Tube Material

Three studies conducted by Klang et al. [17], Undre and Dickinson et al. [31] and McNeely et al. [36] reported that the feeding tube material reduced the bioavailability of the medications due to binding interactions between the medications and the tube materials. One study reported substantial binding of warfarin to G tube materials, reducing drug concentration. [17]. This study outlined factors that influenced sequestration, including pH, temperature, drug concentration, and administration rate. Tolvaptan and tacrolimus showed reduced bioavailability when administered via NG, attributed to insolubility and adsorption to tube materials [31, 36]. Tolvaptan forms an unstable suspension when crushed and administered via NG tube, with 11% sequestered by tube materials in vitro, resulting in a 25% lower AUC (Area Under the Curve) in vivo compared to intact tablets [36]. A similar outcome was observed in an in vivo study on tacrolimus, which demonstrated that using polyvinyl chloride (PVC) free tubing reduced drug adsorption. However, despite this precaution, a portion of the drug may still adhere to the tubing surface, potentially compromising its bioavailability [31].

Buffering Agents

Pantoprazole bioavailability was maintained when tablets were crushed and buffered with sodium hydrogen carbonate, but suspending the drug in sodium bicarbonate solution decreased bioavailability (AUC) by 25%, highlighting the importance of buffering for acid‐labile drugs [37].

Site of Administration

One of the included studies conducted by Vincent et al. [23] evaluated trovafloxacin's bioavailability based on two different administration sites. This study found that duodenal administration reduced AUC by 31% and Cmax (Maximum Concentration) by 30% compared to gastric administration [23].

Dosage Form

Two of the included studies investigated the absorption of crushed clopidogrel tablets and suspension of prolonged‐release tacrolimus capsules via NG tubes [31, 38]. It was noted that clopidogrel's total 24‐h absorption remained unchanged, suggesting no loss of efficacy [38]. For tacrolimus, the immediate‐release component of the prolonged‐release capsules dissolved before administration, resulting in faster absorption [31].

Tube Diameter

Various types and sizes of feeding tubes were used across the included studies. A G tube (12 Fr) was reported in one study [17], while another utilized PEG tubes in sizes 8, 12, 20, and 24 Fr [30]. Two studies employed multiple tube one used NG tubes (8, 14, and 16 Fr) and a G tube (20 Fr) [28], and the other used an NG tube (8 Fr), a G tube (12 Fr), and a J tube (12 Fr). The remaining 20 studies used NG tubes exclusively, with diameters ranging from 5 to 18 Fr. A study by Hoover et al., found that smaller feeding tubes, such as 8 Fr, improve patient comfort but carry a higher risk of clogging, which can reduce medication bioavailability [18]. In contrast, larger tubes like 12 Fr are less likely to clog but may cause more discomfort. Silicone tubes, which require thicker walls for flexibility, have narrower lumens compared to PVC or polyurethane tubes of the same size. Small‐bore tubes (5–12 Fr) are commonly used clinically but are more prone to obstruction. Clogging rates were low for NG tubes (2%–4% for 30 mg doses), whereas G tubes showed higher clogging rates (17%–33%), mainly near the gastric balloon [18]. The J tubes did not clog but retained medication particles, which might increase clog risk over repeated use [18]. Other studies have shown that tube size does not significantly affect medication stability or delivery, with drug recovery consistently exceeding 98% across various tube sizes [24, 25, 28, 30].

Preparation Method

One study compared different techniques for crushing apixaban tablets and found that all resulting suspensions met the acceptable range of 90%–110% of the label claimed concentration. The percentage of the label claim recovered using the mortar and pestle method, crushing syringe, and pill crusher was 98.8% ± 2.0%, 98.0% ± 6.8%, and 94.0% ± 2.8%, respectively [25]. The mortar and pestle method yielded the most accurate and consistent results, whereas the pill crusher led to material loss during preparation, and the crushing syringe method showed substantial variability among samples [25].

Discussion

Significance of Findings

This systematic review provides robust evidence that enteral feeding tube administration can significantly influence medication stability and bioavailability. A total of 29.1% of the included studies reported either a reduction or an increase in medication bioavailability or absorption when administered via feeding tubes. These findings highlight the clinical importance of considering drug‐specific properties, tube characteristics, and preparation techniques when administering medications in patients reliant on enteral feeding.

Notably, 20.8% of included medications demonstrated reduced bioavailability, primarily due to physicochemical interactions with the tube material. Warfarin and tolvaptan, for instance, showed marked reductions in bioavailability, likely attributed to drug adsorption onto the inner surfaces of feeding tubes—particularly PVC [17, 36]. This is consistent with previous pharmacokinetic research demonstrating that lipophilic and protein‐bound drugs are more susceptible to adhesion in tubing [39]. Tacrolimus, even in PVC‐free environments, exhibited similar losses, reinforcing that material composition alone may not mitigate the risk [17].

In contrary, certain medications such as clopidogrel appeared to benefit from tube administration, with enhanced absorption observed in some studies [38]. This may be related to the increased surface area provided by crushing the tablet, which enhances dissolution and potentially improves bioavailability in the upper gastrointestinal tract. However, such advantages are highly drug‐specific and may be offset by the risk of dose variability or tube obstruction if particle size is not adequately controlled.

The site of drug administration also was mentioned as another factor. For example, trovafloxacin administered into the duodenum showed reduced systemic exposure, possibly due to differences in pH, enzymatic activity, and the presence of efflux transporters in the small intestine compared to gastric administration [23]. These findings suggest that the pharmacological effects of medications may vary not only by delivery route but also by anatomical location, and that assumptions of equivalence between oral and enteral administration are not always valid.

Importantly, some drugs including omeprazole and garenoxacin demonstrated stability across different feeding tube types and sites of delivery [20, 21]. This suggests that while some medications are adversely affected by enteral tube administration, others may remain stable and bioavailable, particularly if they are water‐soluble, stable at gastric pH, or have minimal first‐pass metabolism.

Preparation methods were also influential. Crushing techniques, particularly using mortar and pestle, yielded more homogeneous suspensions than commercial pill crushers or crushing syringes [25]. Heterogeneous particle size can affect not only drug delivery but also tube patency, especially in small‐bore tubes (5–12 Fr). Smaller‐bore tubes are generally preferred for comfort, but they are more susceptible to clogging, particularly when drugs are inadequately prepared [18].

Among 24 studies, seven studies addressed proton pump inhibitors (PPIs). Five of these studies showed bioequivalence between the solid oral formulation and the liquid formulation [9, 18, 19, 21, 28]. However, there were exceptions in two studies for pantoprazole tablets. Ferron et al. [37] reported a 25% reduction in bioavailability for the sodium bicarbonate formulation compared to the enteric‐coated tablet while Ley et al. [32] demonstrated that magaldrate provided effective buffering without achieving bioequivalence, compared with crushed pantoprazole with sodium hydrogen carbonate which was bioequivalent.

For medications with a wide safety margin, such as PPIs, small variations in bioavailability do not have a significant impact. However, for drugs with a narrow therapeutic range such as warfarin, tacrolimus, or certain anticoagulants, even minor changes can influence both efficacy and safety. For example, warfarin may adhere to feeding tube materials, reducing its effect [17], Therefore, close monitoring, like checking the international normalized ratio (INR), is important. To minimize the risk of underdosing or overdosing protocols for medications such as warfarin and tacrolimus should include clear instructions on flushing procedures, timing of administration, and the appropriate site of delivery.

Another insight from this review is that despite variability in tube size, the percentage of drug recovery remained high (typically > 98%) in well‐prepared suspensions, suggesting that when standardized protocols are followed, medication loss can be minimized [24, 25, 28, 30]. However, practical issues such as residual volume and tube flushing technique were not consistently reported across studies, making it difficult to draw conclusions about the influence of administration practices on stability.

Taken together, these findings stress the need for individualized administration protocols based on drug characteristics, tube materials, site of delivery, and preparation techniques. They also underscore a broader issue namely, the limited generalisability of standard oral dosing guidelines to patients on enteral nutrition, a population that frequently includes the elderly, critically ill, or those with multiple comorbidities.

Limitations

There are important limitations to consider; the exclusive focus on healthy adult populations limits the applicability of findings to pediatric, geriatric, and acutely ill cohorts. These groups may exhibit altered pharmacokinetics due to disease state, organ dysfunction, or concurrent medication use. Another point to consider is that five of the reviewed studies did not provide a reason for excluding females [20, 22, 31, 32, 37]. In general, medical research often suggests that women's hormonal fluctuations are viewed as unpredictable and may introduce variability which may affect the accuracy of results [40].

It is worth noting, by excluding studies involving food co‐administration, this review may not capture the full spectrum of interactions encountered in clinical practice, where enteral feeds are often administered continuously [41]. Similarly, the exclusion of non‐English language studies may have introduced selection bias, potentially overlooking relevant international evidence.

Finally, the inclusion of only solid oral formulations restricts the scope of the findings. Medications administered sublingually, buccally, or intravenously were not considered, yet may represent important alternatives when tube administration is not feasible.

Directions for Future Research

To strengthen clinical guidance, future studies should adopt more rigorous methodological designs and include broader patient populations, particularly those with chronic illnesses, altered gastrointestinal physiology, or complex medication regimens. Investigations should also explore the long‐term stability and pharmacokinetic profiles of medications administered through various tube types and sizes, including their interaction with tube materials. Standardized protocols for drug preparation and flushing techniques are needed to reduce variability across studies and practice settings. Furthermore, interdisciplinary collaboration among pharmacists, clinicians, and biomedical engineers may foster innovations in drug formulation and tube design that improve safety and therapeutic outcomes for patients dependent on enteral feeding.

Conclusion

The administration of medications via enteral feeding tubes presents a complex interplay of factors that can influence therapeutic effectiveness. Although current evidence offers valuable insights into formulation behaviors and administration practices, it also underscores the need for cautious clinical judgment. Safe and effective drug delivery in this context requires an integrated understanding of pharmacological properties, tube characteristics, and preparation techniques. By synthesizing the existing literature, this review contributes to the broader effort to optimize medication use in patients requiring enteral support and reinforces the importance of tailored, evidence‐based protocols in clinical practice.

Author Contributions

L.A. and W.S. wrote the manuscript. A.A. and W.S. designed the research. L.A., L.B. and W.S. performed the research. L.A., L.B. and W.S. analyzed the data.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information