Preliminary investigation of the thermal antinociceptive effects of codeine in cats

Abstract

Objectives

The aim of this study was to evaluate the potential thermal antinociceptive effects of oral administration of a single dose of codeine in cats compared with positive (buprenorphine) and negative (saline 0.9%) controls.

Methods

Six adult healthy cats weighing 5.14 ± 0.6 kg were used. Skin temperature and thermal thresholds (TTs) were evaluated using a wireless device (Topcat Metrology) at baseline, 0.5, 1, 3, 6 and 10 h after treatment. In period 1, TTs were evaluated after subcutaneous administration of saline 0.9%. In period 2, cats were administered either oral codeine (10 mg total, 2.0 ± 0.2 mg/kg) or buccal buprenorphine (0.04 mg/kg) in a cross-over, blinded study design. Half of the volume of buprenorphine was administered into each cheek pouch. Δ TT (difference between TTs after and before treatment) was used for data comparison. Mean ± SD data were analyzed using one-way ANOVA followed by Dunnett’s or Tukey’s test when appropriate (P <0.05).

Results

Adverse effects did not occur in any group. Skin temperature was not different between groups nor over time. Temporal changes in TTs were not observed after saline or codeine. Buprenorphine increased Δ TT at 3 h (2.7 ± 3.3°C) when compared with baseline or saline (P <0.05). For buprenorphine, TTs were not >47.6°C at any time point in four cats. The mean highest temperature recorded in the two other cats in that group was 54.5 and 52.8°C at 3 h.

Conclusions and clinical relevance

At the dose administered, codeine did not produce thermal antinociception. Mild increases in TT after buccal buprenorphine might be related to the first-pass effect after drug swallowing, drug spillage during administration and/or individual variability. These factors should be taken in to consideration when administering buprenorphine by this route in the clinical setting.

Short Communication

Subcutaneous administration of codeine has been advocated for the treatment of postoperative pain in dogs. ¹ The mechanism of action of this drug is not fully elucidated. In other species, its analgesic effects appear to be related to its metabolites, such as codeine-6-glucuronide, norcodeine and morphine. ² Clinical effectiveness or pharmacokinetic (PK) profile of codeine has not been reported in the cat. The aim of this study was to evaluate the thermal antinociceptive effects of oral administration of a single dose of codeine in cats compared with positive (buprenorphine) and negative (saline 0.9%) controls.

Materials and methods

This study was approved by the local animal care committee of the Faculty of Veterinary Medicine, University of Montreal (14-Rech-1741). Six healthy adult domestic shorthair cats (five males, one female), weighing 5.14 ± 0.6 kg were included in this study. Cats were housed according to the Canadian Council on Animal Care guidelines. During testing, they were housed individually in adjacent cages in a room with temperature and humidity control.

Antinociception was evaluated using a thermal threshold (TT) system device using an infra-red wireless remote control (Topcat Metrology). Cats had been well handled and familiarized with the testing procedure prior to the study. Briefly, a probe containing a heating element and temperature sensor was held against the shaved skin of the lateral aspect of the thorax by an elasticated band as previously described, ³ and skin temperature (ST) was recorded. For the TT testing, a ramped heat stimulus (0.6°C/s) was then applied via a handheld remote unit and stopped when a behavior response was observed (jumping, flinching, vocalization or turning towards the probe), and the recorded temperature was considered the TT. If no reaction was seen, a safety cut-off of 55°C was used to prevent burns. The probe was calibrated before the study according to the manufacturer, and a single observer performed TT testing.

Prior to treatment administration, three recordings were performed at 15 min intervals and their mean value taken as the baseline TT. Treatments were then administered, and TTs were measured at 0.5, 1, 3, 6 and 10 h after drug dosing. At 3, 6 and 10 h, two recordings were performed at 15 min intervals, and their mean value taken as the TT for that time point. Adverse effects were monitored and recorded.

The study was performed in two periods with a 14 day interval between treatments. Cats were not fasted before drug administration. In period 1, TTs were recorded after subcutaneous administration of saline 0.9% between the shoulder blades. In period 2, cats were administered either oral codeine (10 mg total, 2.0 ± 0.2 mg/kg) (Codeine phosphate 10 mg; Gentès & Bolduc) using a commercial pet-piller device (H-bar-S manufacturing, CDMV) or buccal buprenorphine (0.04 mg/kg) (Vetergesic; Champion Alstoe Animal Health) using a 1 ml syringe in a randomized blinded cross-over design. Codeine was compounded in a capsule that was made of gelatin (size number 4) in a lactose excipient (146 mg of lactose/capsule). A water flush was not given to the cat following the administration of codeine. Half of the volume of buprenorphine was administered into each cheek pouch by an observer (AML) who was not involved in testing. Δ TT (difference between TT after and before treatment) was taken as the outcome variable for comparison between groups.

Normal distribution of data was confirmed using the Shapiro–Wilk test. For each treatment, ST and TT were analyzed for temporal changes with one-way repeated measures ANOVA, followed by the Dunnett’s test when appropriate. Treatments were compared using a one-way ANOVA followed by the Tukey’s test at each time point (GraphPad Prism 4; GraphPad Software). Values are reported as mean ± SD (P <0.05).

Results

Adverse effects were not observed after any treatment. The volume of administration for buprenorphine was 0.69 ± 0.08 ml. Drug spillage occurred in one cat, while excessive salivation was observed in another cat during buprenorphine administration. In addition, three cats displayed behavioral signs of euphoria such as increased kneading, purring, rolling and/or rubbing between 1 h and 3 h after buprenorphine treatment.

Baseline ST and TT (54 observations in total for each) were 36.7 °C ± 0.4 °C and 45.2 °C ± 1.8°C, respectively. Overall, ST was not significantly different among treatments nor over time. Temporal changes in TT were not observed after saline or codeine at any time point. Buprenorphine increased TT at 3 h (47.8 °C ± 4.8 °C) when compared with baseline or saline (P <0.05) (Figure 1). For this treatment, TTs were not >47.6°C at any time point in four cats. The mean highest temperatures recorded in the two other cats in that group were 54.5°C and 52.8°C at 3 h.

Figure 1.

Mean ± SD of delta thermal threshold (TT; difference between thermal threshold after and before treatment) following either oral administration of codeine (10 mg), buccal administration of buprenorphine at 0.04 mg/kg or subcutaneous injection of saline 0.9% in conscious cats. *Significantly different from baseline values and saline

Discussion

To our knowledge, this is the first report on the antinociceptive effects of codeine in the cat. In this study, thermal antinociception was not detected after a single dose of orally administered codeine in cats, and this could be explained by a combination of factors as follows. The low efficacy of codeine might be related to its poor bioavailability as observed after oral administration of a similar dose in dogs.^2,4,5 Poor bioavailability would explain the lack of antinociception of oral codeine in our study and further PK study is warranted to confirm this hypothesis in cats. The seemingly low analgesic efficacy of codeine could be influenced by its metabolism. The metabolites of codeine such as morphine, norcodeine and codeine-6-glucuronide are thought to be responsible for its analgesic effects. ² Humans produce different amounts of these metabolites owing to polymorphisms within metabolic enzymes, such as cytochrome P450, that mediate opioid metabolism. Ultimately, there is large variability in analgesic responses, ⁶ and the same could occur with cats. Besides, one could argue that thermal testing may not be ideal for the evaluation of antinociception after codeine. However, the antinociceptive effects of different opioids have been demonstrated using thermal antinoception in cats, ⁷ and the model seems to be appropriate for the study of opioid analgesia. The route of administration could affect the PKs and pharmacodynamics and therefore the analgesic effects of codeine as observed with buprenorphine in cats. ⁸ In fact, subcutaneous administration of codeine provided postoperative analgesia in dogs undergoing mandibulectomy or maxilectomy. ¹ Dosage regimens for codeine have not been reported in cats. Our dose (~2 mg/kg) may not have been appropriate as it was based on a canine study. ² It is unclear if and how codeine was absorbed by the gastrointestinal tract as no PK data are available. For these aforementioned reasons, this study may be considered a preliminary investigation using a single dose, route of administration and nociceptive model without PK data.

Buprenorphine has been widely investigated in cats, ⁹ using the same antinociceptive model and route of administration. In fact, buprenorphine significantly increased TT after buccal administration in different studies,^10,11 and, for this reason, it was chosen to be our positive control treatment. Therefore, it is surprising that thermal antinociception was significantly recorded at only 3 h when compared with baseline or saline. However, similar findings were observed in a recent study where buccal administration of buprenorphine significantly increased TT at only one time point (44 mins after drug administration) when compared with baseline. ¹² Inconsistent thermal antinociception after buprenorphine in this study might be explained by one or more factors, including individual variation in PK data resulting in lower drug bioavailability in some individuals, ¹³ drug spillage, different formulation of the drug and the first-pass effect. Buccal administration of buprenorphine implies that the drug is absorbed by the oral mucosa into the bloodstream via capillaries bypassing the portal vein. If, instead, the drug or a portion of the drug is swallowed, it will undergo the first-pass effect, which is characterized by hepatic metabolism before it enters the systemic circulation. ¹⁴ This effect may have occurred because large volumes of buprenorphine were administered. In two cats, buprenorphine administration was difficult. Drug spillage and excessive salivation were observed, and it is likely that these cats did not receive a full dose of the opioid, which could explain the lack of effect. However, lower doses of buprenorphine have been administered buccally, resulting in significant thermal antinociception.^10,11 The dose used herein was based on a recent study that showed a lower bioavailability of 0.02 mg/kg of buprenorphine than previously reported.^10,13 A twofold dose increase was chosen to maximize bioavailability and, ultimately, antinociception of the drug.

Our partial cross-over study design might have affected the results. Treatments were divided into two periods because this was initially a PK study, and jugular catheter placement and blood collection in a negative control group was deemed to be unnecessary. However, the PK study was not performed owing to reasons unrelated to this report, and we continued to collect data for codeine and buprenorphine in period 2. For ethical reasons, it was decided that TT re-testing after saline 0.9% using the same research cats under the same experimental conditions and study protocol would have been unnecessary. Therefore, the observer was not blinded to the treatment in period 1 and bias may have been introduced in our study. On the other hand, one may argue that TT testing uses a clear behavioral response endpoint that may minimize bias.

Conclusions

At the dose administered, oral administration of codeine did not produce thermal antinociception. Minor increases in TT after buccal buprenorphine might be related to first-pass effect after drug swallowing, drug spillage during administration and/or individual variability. These factors should be taken into consideration when administering buprenorphine by this route in the clinical setting.