Abstract
Objective—To evaluate the effects of morphine administration for 6 days on gastrointestinal tract function in healthy adult horses.
Animals—5 horses.
Procedures—Horses were randomly allocated into 2 groups in a crossover study. Horses in the treatment group received morphine sulfate at a dosage of 0.5 mg/kg, IV, every 12 hours for 6 days. Horses in the control group received saline (0.9% NaCl) solution at a dosage of 10 mL, IV, every 12 hours for 6 days. Variables assessed included defecation frequency, weight of feces produced, intestinal transit time (evaluated by use of barium-filled spheres and radiographic detection in feces), fecal moisture content, borborygmus score, and signs of CNS excitement and colic.
Results—Administration of morphine resulted in gastrointestinal tract dysfunction for 6 hours after each injection. During those 6 hours, mean ± SD defecation frequency decreased from 3.1 ± 1 bowel movements in control horses to 0.9 ± 0.5 bowel movements in treated horses, weight of feces decreased from 4.1 ± 0.7 kg to 1.1 ± 0.7 kg, fecal moisture content decreased from 76 ± 2.7% to 73.5 ± 2.9%, and borborygmus score decreased from 13.2 ± 2.9 to 6.3 ± 3.9. Mean gastrointestinal transit time was also increased, compared with transit times in control horses.
Conclusions and Clinical Relevance—Morphine administered at 0.5 mg/kg twice daily decreased propulsive motility and moisture content in the gastrointestinal tract lumen. These effects may predispose treated horses to development of ileus and constipation.
Horses with severe musculoskeletal or soft tissue injuries often require potent and prolonged analgesia. Unfortunately, the pharmaceutical options for equine clinicians are limited, and drugs (such as morphine) that are available for use can have adverse effects that create additional complications in alreadycompromised animals.1–3 Daily opioid use in humans can decrease coordinated gastrointestinal tract motility, increase transit time of ingesta through the intestinal tract, and increase absorption of fluid from intestinal contents.4 Similar to the outcome of adverse effects that occur in humans, these effects may lead to impaction colic in horses.5,6
Opioid receptors are distributed throughout the CNS and gastrointestinal tract. Generally, OP3 or μ receptors7,8 predominate in the submucosal plexus, whereas in rats, κ receptors are densely expressed in the myenteric plexus.9 Stimulation of opioid receptors at the level of the CNS induces analgesia. Stimulation of the same receptors in the gastrointestinal tract causes alterations in motility, secretion, absorption, and blood flow.5 Morphine administration delays gastric emptying and decreases peristaltic activity by inhibiting the release of acetylcholine from the myenteric plexus, thereby increasing transit time. In rats and humans8,10,11 morphine also reduces intestinal secretory activity while increasing intestinal fluid absorption, leading to constipation. These gastrointestinal effects appear to affect all species that have been investigated, although the extent to which secretory activity is decreased appears to be species specific. Although morphine-induced ileus affects all portions of the intestinal tract, the colon is more severely affected in humans. Restoration of colonic motility appears to be the limiting factor for resolution of ileus.7 Constipation is a clinically important problem in 90% of humans treated with opioids and negatively impacts the quality of life in patients with terminal disease.4
To the authors' knowledge, published information pertaining to the effects of morphine administration on intestinal transit time and luminal moisture content in equids is limited. Gastrointestinal tract transit time appeared to be modified by morphine in a study12 of the effects of antidiarrheal drugs. Intestinal myoelectrical activity is substantially suppressed in all segments of the intestinal tract by morphine administration.13,14 The objective of the present study was to determine the effects of IV administered morphine on defecation pattern, fecal moisture content, and intestinal transit time in healthy horses.
Materials and Methods
Five healthy adult geldings were used in a crossover study. Two horses were Thoroughbreds, 2 were Quarter Horses, and 1 was an Irish Sport Horse; horses' mean age was 9 ± 4 years. To facilitate acclimatization to the environment in which they would be housed during the study, horses were moved to a stall with rubber flooring 48 hours before the initiation of each experimental period. Horses were fed a diet of alfalfa and grass hays twice daily in a hay net. Water and hay were available ad libitum throughout the study. The study was performed in accordance with guidelines stipulated by the University of California-Davis Institutional Animal Care and Use Committee.
The treatment group received morphine sulfate (0.5 mg/kg, IV, q 12 h) for 6 days, whereas controls received an equivalent volume of saline (0.9% NaCl) solution (10 mL, IV, q 12 h) for 6 days. Injections were administered daily at 8:00AM and 8:00 PM. Horses received treatments in random order. Horses were concurrently being used in another study15 in which an opioid antagonist was given to reverse the morphine effects.
Data collection—On the morning of the third day after initiation of morphine or placebo treatment, 200 BISsa (sphere diameter, 3.2 mm; weight, 20 mg) were administered to each horse via nasogastric tube. Feces were collected every 2 hours for the next 4 days. At least 14 days elapsed between trials, at which point horses switched groups. The following variables were recorded: defecation frequency, weight of feces produced, fecal moisture content, intestinal transit time, borborygmus score, signs of colic, and signs of CNS stimulation or excitement (ie, behavior).
For determination of defecation frequency, the number of bowel movements was recorded every 2 hours for 3 days. For determination of the weight of feces produced, manure was weighed on a calibrated scale shortly after collection every 2 hours, so that wet weight was measured. For fecal moisture content, a representative sample of approximately 100 g from each bowel movement during the 3 days was weighed on a calibrated scale. Samples were dehydrated in an oven at 120°C for 24 hours and weighed again, and the percentage of water in each sample was calculated (results of preliminary trials in the authors' laboratory indicated that 14 to 18 hours of dehydration under those conditions are sufficient to fully dehydrate 100 g of equine feces). For determination of intestinal transit time, the time required for passage of the BISs into feces was assessed via methods described16 for use in horses. In brief, all feces collected for 4 days were radiographed and the number of BISs detected was recorded. Times for the first appearance of BISs in feces (T1) and for the appearance of 10% (T10), 25% (T25), 50% (T50), 75% (T75), and 90% (T90) of BISs were reported and compared.
For calculation of borborygmus scores, intestinal sounds were assessed by auscultating each of 4 abdominal quadrants for a 1-minute period twice daily for 3 days. Quadrants were the dorsal and ventral regions of the abdomen caudal to the ribs, on each side. Scoring was performed according to a scheme previously used in horses,17–19 although the methodology was modified so as to enable detection of not only a decrease in the frequency of intestinal sounds but also an increase in the frequency of intestinal sounds (Appendix 1). Borborygmus scores were assigned 2 and 8 hours after morning administrations of the drug or placebo. During these examinations, heart rate, respiratory rate, behavior in the stall, and signs of abdominal discomfort were also noted and recorded (Appendix 2).
Statistical analysis—Statistical analysis was performed by use of the Student t test or repeated-measures ANOVA and a post hoc Bonferroni test to compare values between the control and treatment groups. Data were reported as mean ± SD. Significance was set at P < 0.05.
Results
Frequency of defecation and weight of feces—In the control group, all horses defecated throughout the day, with a mean ± SD number of 13.1 ± 0.2 (range, 6 to 31) defecations/24-h period (1.1 ± 0.3 defecations every 2 hours), with no apparent temporal association with injections (Figure 1). Mean weight of feces produced per defecation was 1.0 ± 0.1 kg (range, 0.9 to 1.2 kg), with a mean total 24-hour manure production of 12.4 ± 0.3 kg. Morphine significantly (P < 0.01) decreased the number of bowel movements during the 6 hours after administration (3.1 ± 0.9 bowel movements in control horses vs 0.9 ± 0.5 bowel movements in horses receiving morphine). Morphine also significantly (P = 0.02) decreased the mean weight of feces produced during a 24-hour period from 12.4 ± 0.3 kg in controls to 9.4 ± 0.5 kg in treated horses, and decreased the total weights of feces produced during 3 days (Figure 2). A characteristic pattern of defecation was observed among treated horses in that few bowel movements occurred during the first 6 hours after morphine administration, but a rebound effect on defecation was observed after that period. The number of defecations and weight of feces produced during the first 6 hours after morphine administration were 0.9 ± 0.1 and 1.1 ± 0.2 kg, respectively. During the rebound period of defecation, the number of defecations and weight of feces increased to 2.8 ± 0.2 and 3.6 ± 0.3 kg, respectively (P < 0.01).
Mean ± SD number of bowel movements and 24 hour pattern of defecation frequency in 5 healthy horses that received morphine (0.5 mg/kg, IV, q 12 h) or placebo for 6 days. Values were obtained by monitoring horses' bowel movements every 2 hours on days 3, 4, and 5; each data point represents the mean ± SD value from all 5 horses at each 2-hour time point for those 3 days. Arrows indicate times at which injections of saline (0.9% NaCl) solution (control horses) or morphine (treatment horses) were administered.
Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.992
Cumulative fecal weight over the 3-day period of data collection in the same horses as in Figure 1. Arrows indicate times at which injections were administered.
Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.992
Fecal moisture content—Fecal water content for control horses was 76.1 ± 2.9%; that value did not vary during the course of the day. Fecal composition as determined over a 24-hour period was 9.4 ± 0.4 kg (or liters) of water and 3 ± 0.2 kg of dry matter. Mean water content in feces decreased (P < 0.01) to 73.5 ± 2.9% during the period of morphine administration (Figure 3). Moreover, feces from horses in the morphine group were frequently covered with mucus, suggesting stasis in the terminal portion of the colon and rectum.
Mean ± SD values for fecal moisture content in the same horses as in Figures 1 and 2. **Represents a significant difference (P < 0.01).
Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.992
Intestinal transit time—Intestinal transit time was determined by counting the number of BISs in feces. The earliest point at which BISs were detected was 10 hours after administration in the control horses. The cumulative number of detected BISs increased in a sigmoid pattern until a plateau was reached 60 hours after administration. Values for T10, T25, T50, T75, and T90 were 16, 22, 38, 54, and 80 hours, respectively. Four days (96 hours) after administration, 186 ± 2 BISs had been counted in feces. Thus, the mean intestinal transit time required for excretion of 90% of the BISs in control horses was 80 hours (Figure 4).
Recovery of BISs from feces in the same horses as in Figures 1, 2, and 3. The cumulative number of BISs recovered in feces was used as an indicator of intestinal transit time. Arrows indicate times at which injections were administered.
Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.992
Morphine administration resulted in a shifting of the BIS fecal recovery curve to the right (P < 0.01). The cumulative number of BISs recovered increased in a sigmoid pattern and reached a plateau at 78 hours. The first BIS (T1) recovered in treated horses appeared at 32 hours, representing a 22-hour delay, compared with times required for first recovery of BISs in control horses (P < 0.01). Recovery of BISs was delayed for all measurement times: T10, T25, T50, T75, and T90 equalled 32, 48, 58, 68, and > 96 hours, respectively (P < 0.01); Figure 4). At the end of data collection at 96 hours, 177 ± 2 BISs had been recovered. The gastrointestinal transit time required for excretion of 90% of the BISs in horses treated with morphine was > 96 hours. Each time morphine was administered during the linear portion of the curve, a delay or decline in the slope of the curve was observed for 4 to 6 hours.
Borborygmus score—Auscultation of the abdomen 2 hours after injections of saline solution or morphine yielded mean borborygmus scores of 13.2 ± 2.9 in control horses and 6.3 ± 3.9 in treated horses. However, 8 hours after morphine administration, the difference in borborygmus scores between the groups was small (15 ± 1.2 in control horses vs 13.2 ± 2.8 in treated horses).
Behavioral changes and signs of colic—Mean respiratory rate was unchanged, but mean heart rate increased in treated horses during the period of morphine administration (respiratory rate, 20.2 ± 9.1 breaths/min and 23 ± 8.2 breaths/min in control and morphine-treated horses, respectively [P = 0.2]; heart rate, 33.5 ± 5.5 beats/min and 39.6 ± 7.2 beats/min in control and treated horses, respectively [P < 0.01]). The behavior and colic scores in the morphine group were higher than those in controls on the first day of the study, but scores in the treated group decreased over time and reached values that were similar to those in controls. Morphine administration elicited signs of CNS stimulation, such as pacing around the stall and pawing, for 2 to 4 hours after administration in 3 horses. Scores for pacing and pawing after morphine injections decreased over time. The remaining 2 horses had no signs of transient CNS stimulation. The mean behavior score in control horses was 3. Among the morphine group, 3 horses had a score of 4 for 2 days and a score of 3 on the last day; the remaining 2 horses had a score of 3 throughout the study.
Regarding signs of colic, all control horses had scores of 0; however, among treated horses, 2 had a score of 1 for 1 day and 1 had a score of 1 for 2 days. Behavior and colic scores as evaluated during morphine administration were not analogous (ie, horses with higher colic scores did not also have high behavior scores as a result of pacing or circling).
Discussion
In horses, analgesics are essential for management of various clinical conditions; analgesia is necessary to relieve discomfort associated with injury or surgical procedures, allow for an earlier return to ambulation (including avoiding development of laminitis from mechanical overloading of an initially unaffected limb), facilitate smoother recoveries from general anesthesia, and minimize pain-associated inhibition of gastrointestinal motility.
Use of opioids for analgesia during and after surgery is often approached conservatively by clinicians because of the potential for adverse effects. One of the adverse effects that may complicate treatment in horses is a decrease in gastrointestinal tract motility that results in constipation and colic.2,6,12–14 However, a paucity of information exists regarding prolonged administration of opioids to horses and the clinical relevance of consequent alterations in motility patterns. In the present study, gastrointestinal tract function in clinically normal horses was evaluated during a 6-day period of twice-daily morphine administration. The dose of morphine (0.5 mg/kg) selected for study was higher than that recommended for clinical use in horses. It has been reported2,20 that morphine use in the range of 0.02 to 0.1 mg/kg may induce analgesia. At the University of California-Davis Veterinary Medical Teaching Hospital, doses of 0.05 to 0.1 mg/kg given IV or IM are used for routine analgesia in horses without signs of gastrointestinal tract dysfunction. However, we chose the higher dose of 0.5 mg/kg for this study to increase the chance of eliciting detectable gastrointestinal tract dysfunction without inducing severe colic. In a pilot study conducted to determine the dose to be used in the present study, a dose of 1 mg/kg given IV caused severe signs of colic after the third treatment in 1 of 2 horses. Therefore, the dose was halved with the purpose of being able to maintain administration for a period of 6 days. The ability to detect signs of gastrointestinal dysfunction was important not only to evaluate the effect of high-dose morphine but also to evaluate the effects of a morphine antagonist (Nmethylnaltrexone) in a parallel investigation15.
Administration of morphine at a dosage of 0.5 mg/kg every 12 hours caused consistent changes in behavior, number of bowel movements, weight of feces produced, fecal moisture content, gastrointestinal transit time, and borborygmus. Results indicate that this dose can have deleterious effects on gastrointestinal function for 4 to 6 hours after administration. Determinations of behavior, colic signs, and borborygmus scores were not performed in a blinded fashion; therefore, those data must be interpreted with caution but may serve to corroborate the objective data collected pertaining to weight of feces, number of bowel movements, transit time, and moisture content.
Central nervous system excitation secondary to morphine administration may play a role in mediating the drug's effect on intestinal function, as has been reported in other species.21–23 In ponies and horses, morphine administration elicits increased locomotor activity, signs of apprehension, pawing, headshaking, and restlessness.24–27 However, the role of CNS opioid receptors in alteration of gastrointestinal tract function remains unknown.
To the authors' knowledge, this is the first study undertaken to describe the effects of prolonged parenteral morphine administration on propulsive activity of the gastrointestinal tract and fecal moisture content in horses. Single doses of fentanyl or morphine are known to decrease the frequency of migrating myoelectric complexes from the jejunum and cecocolic segments in ponies during a 3-hour period.13,14 Single doses of morphine also result in suppression of borborygmus, an increase in gastrointestinal transit time, and decreases in fecal water content and volume of feces produced.12,28 Opiate-induced gastrointestinal tract dysfunction appears to occur across species. In humans, dogs, cats, rats, and guinea pigs, morphine delays gastric emptying, increases gastrointestinal transit time, and suppresses intestinal secretion of water and electrolytes.8,29–37 In addition to the inhibitory effects induced by opiates, morphine also causes an increase in the contractile tone of the small intestine circular smooth muscle and stationary bursts.8,35 Those high-amplitude, nonpropulsive contractions may explain the abdominal discomfort observed in some horses. In the present study, some horses developed signs of abdominal discomfort after morphine administration.
Although ileus that results from morphine administration occurs as a result of the drug's effects at both central and peripheral levels of the nervous system, it appears that inhibitory effects at the level of gastrointestinal tract receptors may be the predominant mechanism.35 Neurons of the myenteric plexus, gastrointestinal tract nerve fiber endings, and cells at submucosal borders express mRNA for μ and κ receptors.38,39 Results of pharmacologic studies suggest that μ, κ, and δ opioid receptors are present in the gastrointestinal tract.40 Therefore, it is plausible to assume that opiates may directly affect gastrointestinal tract function and that such mechanisms may explain the dysfunction observed in the present study.5,41–44 In 1 study,37 opioid administration directly into the gastrointestinal tract suppressed neuronal excitability and induced hyperpolarization of myenteric neurons in a reversible manner. Opioids in the gastrointestinal tract inhibit the release of vasoactive intestinal peptide and acetylcholine and increase levels of 5-hydroxytriptamine and catecholamines, which are known modulators of motility and water secretion.5,45–47 Hyperpolarization of and inhibition of neurotransmitter release from cells of the gastrointestinal tract decrease the number of bowel movements, weight of feces produced, transit time, and fecal moisture, as evidenced in the present study.
Six days of continuous opioid exposure could result in drug tolerance with subsequent loss of effect.48,49 Whether there is development of tolerance to opioids in the gastrointestinal tract, however, is uncertain. For example, tolerance to opioids was not detected in a study10 on inhibition of intestinal fluid secretion in rats. However, tolerance was reported to play a role in delayed intestinal transit times observed in response to opioid drugs in rats and mice.50–52 In a clinical setting, chronic administration of opioids to human volunteers did not change the severity of induced constipation over time.53
In horses of the present study, there was no indication of opioid tolerance at the gastrointestinal level in terms of the number of bowel movements, weight of feces produced during treatment, or moisture content. The intensity of behavioral changes (ie, pacing, pawing, and signs of colic) decreased over time with repeated morphine administration. However, because the study was not designed to detect opioid tolerance, conclusions cannot be drawn from those observations.
Signs of opioid withdrawal have been observed after chronic administration in humans and other species. The withdrawal effect consists of rebound intestinal motility with decreased intestinal transit time and possible diarrhea.50 No horses in the present study developed diarrhea when morphine administration was discontinued. A rebound effect was observed only when the morphine effect waned after each injection. Six hours after morphine injection, the number of bowel movements and weight of manure produced increased to values similar to those in control horses.
The present study was performed in healthy horses, and it cannot be predicted what effects, if any, would be different after morphine administration to systemically compromised horses. The effect of illness, anesthesia, and surgery may alter morphine pharmacokinetics, and further studies addressing the effects of morphine in physiologically compromised horses are warranted.
On the basis of results in the present study, morphine administered IV twice daily at a dose of 0.5 mg/kg was associated with increased intestinal transit time and decreased secretion of water into feces. Both mechanisms may lead to constipation and ileus in horses. Exogenous opioids administered for analgesia2,20 or endogenous opioids released in response to surgery or other stressors52,54 may have clinically important deleterious effects in the equine gastrointestinal tract. Further investigations in which clinically relevant doses are evaluated are necessary to determine whether the effects we detected would also be observed at lower doses.
ABBREVIATIONS
| BIS | Barium-impregnated sphere |
Barium impregnated spheres, Precesion Plastic Balls Co, Franklin Park, Ill.
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Summary of observations and scores used to record intestinal sounds over a 1-minute period in each of 4 abdominal quadrants (ie, right dorsal, right ventral, left dorsal, and left ventral quadrants) in horses.
| Score | Criteria |
|---|---|
| 0 | No intestinal sounds auscultated |
| 1 | Low-pitched crepitant sounds with a frequency of ≤ 1/min |
| 2 | Low-pitched crepitant sounds with a frequency > 1/min |
| 3 | Long, loud, gurgling sounds with a frequency of 1/min |
| 4 | Long, loud, gurgling sounds with a frequency of 2 to 4/min |
| 5 | Long, loud, gurgling sounds with a frequency > 4/min |
Summary of observations and scale used to record heart rate, respiratory rate, behavior scores, and colic scores in horses.
| Behavior score | Criteria |
|---|---|
| 0 | Recumbent or nonresponsive |
| 1 | Sedated; head held low with little response to stimuli |
| 2 | Sedated; head held low but responsive to stimuli |
| 3 | Normal mentation; alert and responsive to stimuli |
| 4 | Excited; pacing and pawing |
| 5 | Manic; uncontrollable excitement |
| Colic score | Criteria |
| 0 | No signs of discomfort; normal appearance |
| 1 | Mild signs of pain; pacing and looking at flanks |
| 2 | Signs of pain; pacing, sweating, looking at flanks, and pawing |
| 3 | Signs of severe pain; recumbent and sweating |
