Effects of methadone on gastrointestinal transit time and pH of conscious cats

Abstract

Objectives

The aim of the present study was to evaluate the effects of methadone on esophageal, gastric, total intestinal and overall gastrointestinal (GI) transit times and pH in cats.

Methods

In a randomized, placebo-controlled crossover study, six female domestic shorthair cats were administered a pH capsule via the oral route immediately after a 1 h feeding regimen. Cats were randomly assigned an order to receive two treatments immediately after administration of the pH capsule. Each treatment consisted of one intramuscular (IM) injection: treatment SAL consisted of one injection of 0.9% saline solution (0.06 ml/kg) and treatment MET consisted of one injection of methadone HCl (0.6 mg/kg). pH was used to determine the location of the capsule within the GI tract. Esophageal, gastric and total GI transit times and intestinal transit time were compared between treatments using the Wilcoxon match-pairs signed rank test and paired two-tailed t-test, respectively. Mean esophageal, gastric and intestinal pH were compared using the Wilcoxon match-pairs signed rank test.

Results

There were no significant differences found in esophageal (range 1–96 mins vs 2–144 mins; P = 0.56), gastric (range 907–5473 mins vs 1065–10,414 mins; P = 0.06), intestinal (range 1194–2406 mins vs 928–2541 mins; P = 0.92) and total GI transit times (2,244–6674 mins vs 2191–11,486 mins; P = 0.06) between the SAL and MET treatments. There were no significant differences found in esophageal (range 5.4–6.2 vs 4.1–6.2; P = 0.063), gastric (range 1.3–2.9 vs 1.6–2.9; P >0.99) or intestinal (range 7.1–8.3 vs 6.0–8.3; P = 0.063) pH between the SAL and MET treatments.

Conclusions and relevance

A single 0.6 mg/kg dose of IM methadone did not produce changes in the GI transit time or pH when compared with saline. This dose of methadone can be used safely in cats without opioid-induced GI motility effects; however, other adverse effects may still occur.

Introduction

Opioid analgesics are commonly administered to small animals during the perioperative period because of their potent and versatile analgesic efficacy. ¹ Although effective, opioids can have adverse effects, including bradycardia, hyperthermia, euphoria/dysphoria and gastrointestinal (GI) disturbances such as vomiting and nausea.^{2 –4} In addition, deleterious effects on GI motility have been well documented in humans^{5 –7} and horses.^{8 –10} However, research on the impact of clinically relevant dosages of opioid agonists on GI motility in dogs^{11 –14} and cats^{15 –17} remains limited. Given the widespread use of opioids in acute pain management, understanding their GI effects at therapeutic doses could modify small animal patient management.

Peripheral and central mechanisms associated with the stimulation of agonists of mu (µ)-opioid receptors may impair GI motility. Mu-opioid receptors are found within the enteric nervous system, particularly in the stomach (corpus and antrum), duodenum, jejunum, ileum and proximal and distal colon. ¹⁸ Stimulation of these opioid receptors suppresses neuronal excitability via the inhibition of Ca²⁺ channels, membrane hyperpolarization and decreased cyclic adenosine monophosphate and protein kinase A activity. ¹⁸ This results in decreased release of excitatory neurotransmitters (eg, acetylcholine [Ach], vasoactive intestinal polypeptide and substance P [SP]) from Ach- or SP-containing neurons.^15,19 Clinical effects include reduced GI motility, coordination, secretions, gastric emptying time and propulsive activity but also increases in pyloric and anal sphincter tone contributing to constipation.^15,18,19 The effects of opioids on the large intestine are biphasic: (1) stimulation of colonic motility leading to defecation shortly after administration with (2) a subsequent decrease in colonic propulsive motility and secretions.^20,21

Methadone is a synthetic µ-opioid receptor agonist and is approved for the treatment of acute perioperative pain in cats in Canada and Europe. ²² To the authors’ knowledge, little is known regarding the effects of methadone on the feline GI tract. The objective of this study was to evaluate the effects of methadone on esophageal, gastric, intestinal and overall GI transit times in cats. The secondary objective was to evaluate the effects of methadone on esophageal, gastric, small intestinal and large intestinal pH in cats.

Materials and methods

This prospective, randomized, blinded, placebo-controlled crossover study was approved by the Institutional Animal Care and Use Committee of Texas A&M College of Veterinary Medicine and Biomedical Sciences and conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Animals

Six research-purpose-bred, female spayed domestic shorthair cats aged approximately 4.5 years, with a median body condition score (BCS) of 4/9 (range 4–6) and mean ± SD weight of 3.57 ± 0.6 kg at the start of the study and 3.56 ± 0.6 kg at the end of the study, were included. Cats were weighed before each study session and included when deemed healthy based on routine physical examinations and laboratory tests, including complete blood count, serum biochemistry profile and urinalysis. Exclusion criteria included any history of clinical signs associated with GI disease (ie, vomiting, inappetence, anorexia, ptyalism, constipation or diarrhea), physical examination or diagnostic findings suggestive of systemic or GI disease, including a poor haircoat, BCS of ⩽3/9, muscle wasting or abnormalities on abdominal palpation.

To minimize the impact of stress throughout the study, cats were maintained in their standard housing cages (2.4 m length × 4.8 m width × 3.0 m height) with access to daily environmental enrichment and regular socialization. Routine enrichment included access to scratch pads, climbing towers and feline-specific toys. The temperature, humidity and light schedule of the housing and testing facilities were controlled, with an ambient temperature of 21–22°C, humidity of 55–60% and 12 h light/dark cycle. Routine preventive healthcare, such as vaccination and internal parasite control, was provided on a scheduled basis.

Feeding protocol

The feeding protocol has been previously described elsewhere in a similar study assessing GI transit times and pH of cats. ²³ In brief, cats were fed 50–60 g of a commercial diet (Purina Pro Plan Focus Adult Hairball Management Chicken and Rice formula dry cat food; Nestlé Purina PetCare; 3.7 kcal/g as fed; 38.8% metabolizable energy [ME] and 112 g/1000 kcal protein, 39.8% ME and 47 g/1000 kcal fat, 21.4% ME and 62 g/1000 kcal carbohydrate, 11 g/1000 kcal crude fiber) once a day on the days they did not receive the experimental treatment. During the days of experimental treatment, food was withheld for 24 h before feeding with their historical daily allowance (50–60 g) for 1 h. Food was then removed and a continuously recording pH capsule (Bravo pH capsule, Medtronic) was administered orally (see below). Cats were fed the same food allotment at the same time on subsequent days after treatment until defecation of the capsule. All cats were weighed before feeding and the feed was also weighed before and after the feeding time to calculate energy and total food intake. Water was offered ad libitum throughout the study. Fecal consistency using a fecal scoring system (Nestlé Purina PetCare) as previously described ²⁴ and changes in attitude or behavior were monitored a minimum of twice a day.

GI transit time and pH monitoring system

The pH monitoring system (Bravo pH capsule; Medtronic) (Figure 1) used to record GI transit times and pH has been previously described in cats. ²³ The Bravo pH capsule (6 mm × 5 mm × 25 mm) (Figure 2) records GI pH readings from 0 to 9 every 6 s. Capsule administration was performed using feline-friendly practices with minimal restraint to avoid fear and anxiety associated with pilling. Cats used in this study had been previously acclimated to handling techniques by the same investigators (BS, ES, NT) during other studies. The pH capsule was detached from its delivery device after calibration according to the manufacturer’s instructions and administered orally to determine GI transit times and pH. The pH capsule was administered with a syringe-style pet piller (Bullseye Pillgun; Butler Sales) immediately after the 1 h feeding regimen and followed by syringe administration of up to 15 ml of tap water to facilitate swallowing and passage of the capsule through the esophagus. This procedure was performed for each experimental treatment with a washout period of at least 1 week between treatments. GI pH readings started immediately after oral administration and were acquired continuously until the capsule was eliminated in the feces. The corresponding data receivers were kept on the side of each cat’s cage, out of the cat’s reach, during the data acquisition phase. The pH data were uploaded to a computer using a software package provided by the manufacturer (Reflux 6.1; Medtronic) every 48 h for each monitoring period. The same receiver was used to obtain data from the same cat for each treatment period.

Figure 1

(a) Bravo pH Monitoring systems used for all six cats. (b) Bravo pH monitoring system in use depicting the environmental pH during one cat’s gastric period

Figure 2

Bravo pH capsule in comparison to a roll of 2 inch surgical tape

The pH was used to determine the location of the capsule within the GI tract, as previously described.^23,25 Passage from the esophagus into the stomach was defined by a sharp and persistent decrease in the pH (<4). Gastric transit time was defined as the time of entry into the stomach to the time of entry into the small intestine, denoted by a rapid and persistent increase in pH (>4) accompanied by an increase in pH units (⩾3). Intestinal transit time was defined as the time of entry into the small intestine (detected as a sharp increase in pH), followed by exit from the body. The transition from the small intestine to the large intestine could not be determined due to a similar pH. Therefore, small and large intestinal transit times and pH were described together. To represent proximal (likely small intestine) intestinal pH, data from 1 h after gastric transit were analyzed. For distal (likely large intestine) intestinal pH, data for the 1 h preceding capsule elimination were used.

Treatment protocol

In a crossover design, the six cats were randomly assigned an order to receive two treatments (www.randomizer.org). Two investigators (BS and ES), aware of treatment allocation, organized and administered treatments immediately after oral administration of the pH capsule. Each treatment consisted of one intramuscular (IM) injection into the gluteal muscle using a 25 G needle and 1 ml syringe: treatment SAL consisted of one injection of sterile saline solution (0.06 ml/kg, 0.9% sodium chloride injection USP; Baxter Health) and treatment MET consisted of one injection of methadone HCl (0.6 mg/kg, 10 mg/ml; Bioniche Pharma USA).

Statistical analysis

Normality was assessed using Shapiro–Wilk tests. Net food consumption (in g) on the day of treatment (day 1) and day after treatment (day 2) was compared between treatments via a paired two-tailed t-test. Descriptive statistics of patient weight, GI transit time and pH values were calculated. Data are reported as median (range) or mean ± SD, where appropriate. Esophageal, gastric and total GI transit times were compared between treatments using the Wilcoxon match-pairs signed rank test. Intestinal transit time was compared between treatments using a paired two-tailed t-test. Mean esophageal, gastric and intestinal pH was compared between treatments using the Wilcoxon match-pairs signed rank test. Statistical significance was defined as P <0.05.

Results

There were no significant differences in net food consumption on day 1 (25.8 ± 20.03 g vs 30.4 ± 17.70 g; P = 0.71) or day 2 (37.0 ± 12.8 g vs 33.7 ± 16.5 g; P = 0.72) between the SAL and MET treatments.

Median esophageal, gastric, intestinal and total GI transit times are presented in Figure 3 and Table 1. There were no significant differences found in esophageal (6.5 mins [range 1–96] vs 7.5 mins [range 2–144]; P = 0.56), gastric (1086 mins [range 907–5473] vs 2293 mins [range 1065–10,414]; P = 0.06), intestinal (1399 mins [range 1194–2406] vs 1535 mins [range 928–2541]; P = 0.92) and total GI transit times (3075 mins [range 2244–6674] vs 3676 mins [range 2191–11,486]; P = 0.06) between the SAL and MET treatments.

Figure 3

Box plot of each gastrointestinal (GI) transit time physiologic measurement period – (a) esophageal, (b) gastric, (c) intestinal and (d) total GI tract – when the oral Bravo pH capsule was administered after feeding and immediately before an intramuscular injection of 0.9% NaCl (0.06 ml/kg) or methadone HCl (0.6 mg/kg) in six healthy female cats. Symbols represent the individual transit time value for each cat during each period

Table 1

Reported and significance (P) values for gastrointestinal (GI) transit time (mins) and pH when the oral Bravo pH capsule was administered after feeding and immediately before an intramuscular injection of 0.9% NaCl (0.06 ml/kg) or methadone HCl (0.6 mg/kg) in six healthy female cats

		Esophageal		Gastric		Intestinal		Total GI tract
Transit time (mins)	Saline	6.5 (1–96)	P = 0.56	1086 (907–5473)	P = 0.06	1399 (1194–2406)	P = 0.92	3075 (2244–6674)	P = 0.06
	Methadone	7.5 (2–144)		2293 (1065–10,414)		1535 (928–2541)		3676 (2191–11,486)
pH	Saline	5.8 (5.4–6.2)	P = 0.06	1.9 (1.3–2.9)	P >0.9	8.0 (7.1–8.3)	P = 0.06
	Methadone	5.1 (4.1–6.2)		1.9 (1.6–2.9)		7.4 (6.0–8.3)

Data are median (range)

Esophageal, gastric and intestinal pH are presented in Figure 4 and Table 1. There were no significant differences found in median esophageal (5.8 [range 5.4–6.2] vs 5.1 [range 4.1–6.2]; P = 0.06), gastric (1.9 [range 1.3–2.9] vs 1.9 [range 1.6–2.9]; P >0.9) or intestinal (8.0 [range 7.1–8.3] vs 7.4 [range 6.0–8.3]; P = 0.06) pH between the SAL and MET treatments.

Figure 4

Box plot of each gastrointestinal pH physiologic measurement period – (a) esophageal, (b) gastric and (c) intestinal – when the oral Bravo pH capsule was administered after feeding and immediately before an intramuscular injection of 0.9% NaCl (0.06 ml/kg) or methadone HCl (0.6 mg/kg) in six healthy female cats. Symbols represent the median pH value for each cat during each period

One cat vomited the pH capsule at 1356 mins (22.6 h) after the administration of SAL. GI values associated with this event were not included in the analysis. To maintain adequate and equal values for data analysis, the SAL treatment was repeated in the same cat 7 days after the episode. Vomiting was not observed in cats after the administration of MET.

Discussion

Opioids are commonly administered for acute pain management and sedation across domestic species^1,26,27 and in various clinical settings, from intensive care to perioperative care. Although effective, they can adversely affect GI function in small animal patients, ²⁸ potentially causing vomiting, ileus and constipation. This raises concerns about their GI effects, even as they remain the cornerstone of acute pain management. To date, little information on the effects of opioid administration in cats is available, and this study provides data on the effects of methadone in the GI tract, specifically on transit time and pH changes. This prospective, randomized, experimental trial showed that the administration of a single dose of IM methadone did not significantly change net food consumption, GI transit times or pH in conscious cats. Moreover, adverse effects such as vomiting were not observed in this small cohort of healthy, laboratory-housed cats.

The present results associated with gastric emptying time in cats administered saline are consistent with those reported in a similar study of cats after feeding (1086 mins [range 907–5473] vs 1068 mins [range 484–5521], respectively). ²³ Interestingly, cats receiving methadone in the present study had a median gastric emptying time more than 1000 mins longer (2293 mins [range 1065–10,414]) than these values. ²³ Median total GI transit time was slightly longer (280 mins) in cats administered saline than that reported in the previous study (3075 mins [range 2244–6674] vs 2795 mins [range 926–6563], respectively). ²³ Median total GI transit time in cats administered methadone was more than 600 mins longer, although not significantly different (P = 0.06), when compared with the cats administered saline and those in the previously reported study (3676 mins [range 2191–11,486] vs 3075 mins [range 2244–6674] and 2795 mins [range 926–6563], respectively). ²³ Increasing the sample size could help identify statistically significant differences between cats administered opioids and those left unmedicated. The effects of saline or methadone on GI pH remained consistent with what has been previously reported in fed cats. ²³ In the present study, the one-time administration of methadone at the dose described had little effect on GI transit time in conscious, healthy cats.

A previous study reported the GI effects of administering IM morphine at a low (0.1 mg/kg) and high (1 mg/kg) dose to cats. ²⁹ At the lower dose, morphine accelerated aboral transit time within the cecum and ascending colon, as determined by a smaller area under the time activity curve (AUC), to 65% of control value. ²⁹ In contrast, aboral transit time was increased by 321% in the descending colon compared with control. ²⁹ Morphine at the higher dose delayed cecal and ascending colon transit time in that the AUC increased by 306% compared with control. ²⁹ Buprenorphine, a partial µ-opioid receptor agonist, administered at 0.01 mg/kg IM and in combination with acepromazine (0.1 mg/kg) did not influence orocecal transit times in cats. ³⁰ In the present study, intestinal (small and large) transit time was not affected by the pure µ-opioid receptor agonist methadone. Differentiating transit times between the small and large intestines is not feasible with the Bravo pH capsule when using pH measurements. Factors influencing the observed effects of opioid agonists may include variations in the type, frequency and dose of opioid administration and the method used to assess transit time in cats.

Several previous studies have reported the effects of opioids on the GI tract in dogs. Gastric emptying time was prolonged in dogs administered butorphanol (0.05 mg/kg) and acepromazine (0.1 mg/kg), with higher doses of butorphanol (eg, up to 0.1 mg/kg) also delaying intestinal transit times. ³¹ Intravenous morphine (approximately 0.008 mg/kg) administered continuously over 7 days prolonged the recovery of gastric emptying and intestinal transport after a paralytic state following intra-abdominal surgery. On the other hand, epidural morphine (approximately 0.008 mg/kg) significantly hastened GI recovery when compared with intravenous morphine in the same canine model. ¹⁴ Morphine also induces unusual patterns of contractions (dysmyogenesia and amyogenesia), which contributes to delayed intestinal transit time in dogs. ³² Further studies using morphine and similar methods are necessary in cats.

The study has limitations. Intra- and interindividual variation in GI transit times and pH has previously been described in healthy adult cats. ²³ High degrees of variability were also recorded in the present study for both transit times and pH within treatment groups after capsule administration. Reasons for this variability are published elsewhere, but briefly, variation in body size, caloric and volume intake, and pharmacokinetic/pharmacodynamic response to opioid administration could explain interindividual variability. In addition, inter-/intraindividual variation in gastric transit time was greater in the present study than in other studies using ultrasound or scintigraphy modalities for evaluating gastric emptying in cats.^33,34 This variation may be related to the degree of randomness in when the capsule is propelled through the stomach. In addition, this study evaluated the effects of a single dose of a single opioid. It did not evaluate whether opioid-induced reductions in GI transit times and pH would have occurred with alternative methadone dosing regimens, including intravenous, oral or subcutaneous administration, or with single vs repeated or higher doses. Similarly, this study did not evaluate whether continuous infusion of different opioids (eg, fentanyl, remifentanil) produces changes in the GI tract of cats. The study design involved experimental healthy cats that had been acclimated to the environment and facilities and may not represent a clinical population of cats that are unfamiliar with the hospital setting, leading to fear and anxiety, or are undergoing surgery and anesthesia, including the administration of other medicines with or without effects on the GI tract. Hospitalized cats may be in pain or have comorbidities including GI disease, and the findings may not represent the clinical setting. Further studies are warranted to investigate the effects of various dosage ranges and long-term opioid use for chronic pain management. Cats were fasted for 24 h before treatment to standardize protocol and ensure appetite. This technique was used in previous studies^23,35 and therefore comparisons of the effect of a one-time opioid administration can be discussed.

Conclusions

A single dose of methadone (0.6 mg/kg IM) did not produce changes in GI transit time or pH when compared with IM saline. This dose of methadone can be used safely in cats without opioid-induced GI motility effects. Whether this can be extrapolated from healthy cats undergoing elective or short procedures is unknown. Studies using other opioids with different doses, regimens (bolus vs infusions) and routes of administration are warranted.