The effects of high fat diet consumption on morphine-induced constipation

Abstract

Introduction:

Opioids, prescribed for pain relief or as maintenance therapies for opioid use disorder (OUD), induce constipation, which can lead to medication compliance issues. However, it is not known how dietary manipulation might impact opioid-induced constipation.

Methods:

To test the hypothesis that eating a high fat diet exacerbates opioid-induced constipation, male and female Sprague-Dawley rats (n=8/diet/sex) were fed either a low fat (standard) diet, a high fat/high carbohydrate diet, or a ketogenic diet. Rats were injected with either saline or morphine (1–10 mg/kg) and constipation was measured by counting fecal boli hourly for 6 hours.

Results:

Morphine induced comparable constipation in all groups; however, rats eating a high fat/high carbohydrate or ketogenic diet produced significantly less feces following injections of saline or morphine as compared to rats eating a standard diet (P<0.05).

Conclusion:

Dietary considerations might be important for patients prescribed opioid medications.

1. Introduction

Opioids are prescribed for pain relief (Phillips et al., 2017; Cohen et al., 2023; Murphy et al., 2023; Cofano et al., 2024) and as maintenance therapies for opioid use disorder (OUD; Stotts et al., 2010). However, opioids also induce constipation, even when used acutely (Phillips et al., 2017; Dydyk et al., 2024; Vallerand et al., 2019; Vollebregt et al., 2020; Benyamin et al., 2008), contributing to medication compliance issues (Benaymin et al., 2008; Varrassi et al., 2021; Morgan & Christie, 2011). For example, in one survey, over 50% of patients with pain-related conditions modified their opioid regimen because of constipation (Varrassi et al., 2021), and opioid-induced constipation is associated with a significantly reduced quality of life among patients taking opioid maintenance therapies for OUD (Lugoboni et al., 2016).

Some individuals are already at higher risk for constipation and are prescribed opioids at higher rates than the general population. For example, individuals with metabolic disorders, such as insulin resistance, obesity, and type II diabetes, experience altered gut motility and are prescribed opioids at a higher prevalence than the general population (Stokes et al., 2019; Stokes et al., 2020). The overconsumption of diets that are high in fat and sugar is associated with metabolic dysfunction (Thaker et al., 2017; Gibson, 1996), and these diets are often lower in fiber (Ionita-Mîndrican et al., 2022), which could enhance constipation (Shen et al., 2019). Therefore, it is critical to understand the relationship between dietary habits and opioid-induced constipation.

While consumption of high fat diets is associated with weight gain, certain high fat diets can lead to weight loss (Moreno et al., 2014; Batch et al., 2020). For example, ketogenic diets (which are high in fat but very low in carbohydrates) promote weight loss and improve metabolic markers (Maswood et al., 2023). Further, ketogenic diets have recently been explored in the context of substance use disorder (Wiers et al., 2023; Wiers et al., 2021; Beltran et al., 2024; though see Trinko et al., 2023). The present study explored the impact of consumption of different types of high fat diets on opioid-induced constipation in male and female rats.

2. Materials & Methods

Male and female Sprague-Dawley (N=48) rats (Inotiv, Indianapolis, IN) arrived on PND 23 and were randomly assigned (n=8/diet/sex) to a low fat (i.e., standard) diet (17% kcal from fat, 58% kcal from carbohydrates [13.7% g/kg fiber], 25% kcal from protein), a high fat/high carbohydrate diet (60% kcal from fat, 21.4% kcal from carbohydrates [6.6% g/kg fiber], 18.3% kcal from protein), or a ketogenic diet (90.5% kcal from fat, 0.3% kcal from carbohydrates [8.8% g/kg fiber], 9.2% kcal from protein) on PND 25–27. Experiments were conducted in compliance with the Institutional Animal Care and Use Committee at The University of Texas at El Paso, and in accordance with the 2011 Guide for Care and Use of Laboratory Animals (Institute of Laboratory, Animal Resources on Life Sciences, the National Research Council, and the National Academy of Sciences).

2.1. Procedure

All rats had free access to their respective diets except on testing days. On test days, food was removed 15 hours, and rats were provided access to their diets for 2 hours. The high fat/high carbohydrate and ketogenic chows were homogenized (75 g chow in 120 mL DI water) using an emulsifier (Ninja Power Mixer; Newton, MA), and the standard chow was soaked in water for approximately 1 hour (Gerak et al., 2019). Rats received an intraperitoneal (i.p.) injection of saline or randomized doses of morphine (1, 3.2, and 10 mg/kg) once weekly (beginning PND 31–33) for up to 8 weeks (with each condition evaluated twice). Fecal output was collected and counted hourly throughout the 6-hr session. Fecal boli were counted once an hour for 6 hours, and results are expressed as the cumulative boli count across the 6-hr study (Gerak et al., 2019). Once weekly, body weight and wet chow consumption were measured at the end of the 2-hour feeding period.

3. Drugs

Morphine sulfate was purchased from Sigma-Aldrich (St. Louis, MO), prepared in 0.9% saline, and administered in a volume of 1 ml/kg, i.p.

4. Data Analyses

Body weight was analyzed using a two-way repeated measures ANOVA with diet and week in study as factors. Total boli count was analyzed using a two-way repeated measures ANOVA with diet and dose as factors. Tukey’s post hoc multiple comparisons were used where appropriate, and statistical significance was set to P<0.05.

5. Results

5.1. Body Weight & Food Consumption

Body weight was measured once weekly, on the same day fecal output was assessed, and is presented as group averages in g (±S.E.M.; Fig. 1 A&B). For male rats (Fig. 1A), a two-way repeated measures ANOVA analyzing body weight revealed a significant main effect of week [F (7, 147) = 1872; P<0.0001] and a significant week by diet interaction effect [F (14, 147) = 2.707; P=0.0014]; however, no main effect of diet was revealed. For female rats (Fig. 1B), a two-way repeated measures ANOVA revealed a significant main effect of week [F (7, 147) = 1178; P<0.0001] and a significant week by diet interaction effect [F (14, 147) = 3.286; P=0.0001]; however, no main effect of diet was revealed (P=0.288, NS). That is, throughout the experiment, all rats gained weight without any significant differences among groups based on dietary intake.

Figure 1:

Mean ± SEM body weight in grams (g) in male (A) and female (B) rats eating either standard (closed symbols), high fat/high carbohydrate (open squares), or ketogenic chow (shaded squares). There were no dietary group differences in body weight throughout the study (P>0.05).

5.2. Morphine-Induced Constipation

Total fecal boli count is presented as group averages (±S.E.M.; Fig. 2 A&B). For male rats (Fig. 2A), a two-way repeated measures ANOVA analyzing total fecal boli count revealed significant main effects of dose [F (3, 63) = 136.8; P<0.0001], diet [F (2, 21) = 27.23; P<0.0001], and a significant dose by diet interaction effect [F (6, 63) = 3.595; P=0.0040]. Tukey’s post hoc comparisons tests revealed that following injections of 1, 3.2, and 10 mg/kg morphine (P<0.05) male rats produced less feces as compared to following saline injections. This effect was dose-dependent for male rats eating standard chow; however, these rats produced significantly more feces after all injections (both saline and morphine) than rats eating high fat/high carbohydrate or ketogenic chow (P<0.05). This suggests that all male rats experienced a decrease in fecal output (e.g., constipation) following morphine injections; however, rats eating standard chow produced more feces following injections of saline or morphine than rats eating high fat/high carbohydrate or ketogenic chow.

Figure 2:

Mean ± SEM total (across the 6-hr experiment) fecal output from male (A) and female (B) rats eating either standard (closed symbols), high fat/high carbohydrate (open squares), or ketogenic chow (shaded squares). Morphine induced comparable constipation in all rats; however, rats eating a high fat/high carbohydrate or ketogenic diet produced significantly less feces following injections of saline or morphine as compared to rats eating a standard diet (P<0.05).

For female rats (Fig. 2B), a two-way repeated measures ANOVA analyzing total fecal boli count revealed significant main effects of dose [F (3, 63) = 48.32; P<0.001], diet [F (2,21) = 24.72; P<0.0001], and a significant dose by diet interaction effect [F (6, 63) = 2.52; P=0.030]. Tukey’s post hoc comparisons tests revealed that all female rats produced less feces following injections of 1, 3.2, and 10 mg/kg morphine (P<0.05). Further, female rats eating standard chow produced more feces following injections of saline, 1, 3.2, and 10 mg/kg morphine as compared to rats eating high fat/ high carbohydrate chow or ketogenic chow (P<0.05). This suggests that all female rats experienced a decrease in fecal output (e.g., more constipation) following morphine injections; however, rats eating standard chow produced more feces following injections of saline or morphine than rats eating high fat/high carbohydrate or ketogenic chow.

6. Discussion

In the present study, morphine administration led to constipation for all rats as represented by reduced fecal output, and constipation occurred regardless of body weight, sex, or diet. However, following saline and all doses of morphine, male and female rats eating high fat/high carbohydrate or ketogenic chow produced less feces than rats eating standard chow (Fig 2). For rats eating standard chow, morphine dose-dependently induced constipation (Fig 2). In contrast, overall feces production was reduced to near zero after all doses of morphine tested for rats eating the high fat/ high carbohydrate or ketogenic diets (Fig 2). That is, while the magnitude of constipation appears similar between groups, there appears to be a floor effect for the rats in the high fat dietary conditions, where the ability to visualize dose-dependent effects is limited.

While the fat content was a primary consideration for dietary selection in the present report, these diets also differ considerably regarding their fiber content. For example, the standard chow has more fiber (13.7% fiber g/kg; grain-based diet) than the high fat/high carbohydrate (6.6% fiber g/kg; purified diet) or ketogenic (8.8% fiber g/kg; purified diet) chows. Further, previous work suggests that morphine-induced constipation might be mitigated by eating diets high in fiber (Niwa et al., 2002). However, it is unknown if fiber supplementation might have helped mitigate some of the constipation for rats eating the experimental diets in the present report, although this should be a focus of future work. Understanding the role of dietary fiber intake in mitigating opioid-induced constipation is especially relevant both for individuals who might be at an increased risk for experiencing constipation (i.e., those diagnosed with metabolic disorders) who might be taking opioids for pain management, as well as for individuals with OUD who might explore dietary interventions as a part of their treatment for OUD. There is growing evidence that eating a ketogenic diet might mitigate some of the effects of substance use disorder, at least in the context of alcohol use disorder, such as alcohol craving (Wiers et al., 2021; Wiers et al., 2023) and other reports also suggest potential benefits for opioid withdrawal (Beltran et al., 2024). The results of the present study suggest that for both individuals who might regularly consume high fat diets, as well as for those adopting a ketogenic diet in conjunction with maintenance therapy for OUD, constipation is not only expected but might be particularly severe even following small doses of opioids.

Given that ketogenic diets on their own are associated with low fiber intake (Crosby et al., 2021) and reductions in fecal production, it is particularly important to consider the potential for constipation among patients using opioids for chronic pain management or for maintenance therapy for OUD, as constipation is a known barrier for treatment adherence that can negatively impact quality of life (Varrassi et al., 2021; Lugoboni et al., 2016). Therefore, the present results highlight the critical need for individualized dietary recommendations as a part of comprehensive treatment plans for patients. Further, recommendations should extend past the overall macronutrient level, and specific micronutrient intake should be considered. For example, while limiting overall carbohydrate intake might be beneficial to promote ketosis, the specific type of carbohydrates consumed matter (Holesh et al., 2023). For example, while glucose and other sugars impact glucose metabolism and overall glycemic index, fiber is a non-digestible complex carbohydrate that does not mirror those effects (Holesh et al., 2023). Therefore, fiber supplementation might be an important consideration for mitigating constipation discomfort in those consuming a ketogenic diet, without compromising the benefits of a ketogenic diet as they relate to metabolic markers and potentially substance use disorders. As such, tailored dietary adjustments or supplementation strategies might benefit patients taking opioids for pain management in the context of obesity, as well as those diagnosed with OUD or who are using opioids for maintenance therapy. Future studies investigating the use of high fat diets (including a ketogenic diet) for substance use disorders or metabolic diseases, should consider including patient education and dietary recommendations as part of the overall approach.