10 Dec 2012
ELISA BORTOLAMI, LOUISA SLINGSBY and JOANNA MURRELL discuss the clinical use of methadone in cats, looking at studies evaluating its effectiveness and comparing it to other analgesia choices
THE first part of this article (VT42.19) provided a brief overview of managing acute pain in cats; this part focuses on the use of methadone in cats. Methadone is now licensed for use in cats and it is a useful drug that may increase the effectiveness of analgesia protocols in cats.
Relatively few studies have evaluated methadone in cats. In a clinical study in 1993, cats undergoing ovariohysterectomy received 0.1mg/ kg, 0.3mg/kg or 0.5mg/ kg racemic methadone by intramuscular (IM) injection for premedication1.
Postoperative pain was assessed by behavioural observation, including gentle palpation of the wound. Duration of analgesia in cats receiving the highest dose of methadone (0.5mg/kg) varied between one-and-a-half and six-and-ahalf hours. The authors concluded methadone may be used at dose rates up to 0.5mg/ kg as a premedicant in cats without significant risk of undesirable behavioural changes or intraoperative respiratory depression, when combined with the anaesthetic protocol used in the study.
In a clinical study published in 2004, Bley and colleagues compared the analgesic efficacy of racemic methadone, levo-methadone and dextromoramide, a powerful opioid analgesic structurally related to methadone, administered by IM injection in 76 cats undergoing ovariohysterectomy2. The test drugs were given as part of the premedication regimen (methadone 0.6mg/kg, levomethadone 0.3mg/kg), and a negative control group receiving saline was included in the study design.
Postoperative pain was assessed for four hours after surgery, using assessment of body position and response to wound palpation. Rescue analgesia was provided with levo-methadone (0.1mg/ kg) whenever pain scores exceeded pre-defined criteria. The majority of the cats in the control group (saline) showed signs of pain and received rescue analgesia during the four hours after surgery. Eighteen of the 19 cats given racemic methadone were considered to be comfortable and painfree during the scoring period. Levo-methadone was associated with good analgesia, but also caused agitation and hyperactivity (not seen in the racemic methadone group).
A clinical study published in 2005 (Mollenhoff et al) compared the antinociceptive effects of subcutaneous (SC) carprofen (4mg/kg), levomethadone (0.3mg/kg) and buprenorphine (0.01mg/kg) in cats after orthopaedic surgery for reduction of traumatic fractures of long bones, pelvis or scapula3. The analgesic treatment was continued for five days (in the methadone group, methadone was given every eight hours), the first treatment was at extubation. Pain was assessed for the first eight hours after surgery and then on days two to five, one hour after analgesic administration in the morning and one hour before analgesic administration in the evening. Pain scoring comprised a numerical rating scale (based on clinical assessment of the patient, including palpation of the wound), mechanical nociceptive threshold of the traumatised tissue using a mechanical dynamometer and a visual analogue scale (VAS). Sedation was also scored using a VAS. In this study, the methods used to score analgesia showed all three analgesic treatments provided significant analgesic effectiveness compared to a negative control group. Levo-methadone caused some behavioural changes over the five-day period, but they were not considered to be clinically problematic.
In 2006, methadone was investigated in a well-validated preclinical model used to assess analgesics in cats. Steagall and colleagues compared the effects of three opioids – methadone, morphine and buprenorphine – and a negative control – saline – on thermal and mechanical thresholds in eight cats.
Thermal and mechanical thresholds are tests used to determine the intensity at which the stimulus is perceived to be noxious by the animal (threshold), achieved by application of either a thermal or mechanical stimulus of increasing magnitude to a specific body area4–5. Methadone at 0.2mg/kg was administered subcutaneously.
Thermal thresholds were significantly higher following methadone compared to saline at one to three hours after administration. Mechanical thresholds were significantly higher after methadone administration compared to saline for the first hour after methadone administration. No adverse side effects were noted following methadone administration6. This study indicates a relatively short duration of analgesia, but the methadone was given subcutaneously, which may not be the most effective route of administration.
According to a study in 2011, IV methadone at the dose of 0.3mg/kg significantly decreased minimum alveolar concentration (MAC) of sevoflurane in cats for approximately two hours after administration7.
Finally, a study published in 2011 compared the effects of 0.3mg/kg of racemic methadone administered intravenously with 0.6mg/kg methadone administered by the oral transmucosal route (OTM), a non-painful route of administration that can be useful for cats, particularly for repeated drug administration. Despite lower mean peak plasma concentrations, the duration of antinociception was four hours following OTM administration, compared to two hours following IV administration. Antinociceptive effects were detected 10 minutes after administration in both groups8.
Collectively, these clinical studies provide evidence that methadone is an efficacious analgesic drug when given by a variety of routes, including IV, IM and OTM. Administration of methadone at doses up to 0.6mg/kg does not cause any adverse effects and provides analgesia for approximately four to six hours.
The analgesia and anaesthesia research group at the University of Bristol’s school of veterinary sciences, of which the authors are part, has carried out a series of experimental and clinical studies involving administration of methadone to cats. Data are being analysed and published. They support the findings of previous clinical studies and confirm the utility of methadone for analgesia in cats.
In the authors’ experience, in many clinical situations methadone is preferred over other opioids in cats.
Major decision making involves whether to choose a partial µ-receptor agonist such as buprenorphine, or a full µ-agonist such as pethidine, methadone or morphine. Full µ-agonists with a medium duration of action are indicated for the provision of analgesia in cases of moderate to severe pain, or to treat mild pain when a uni-modal analgesia technique is used (for example, in cats in which administration of a NSAID is contraindicated). Pethidine is licensed in cats, but has a short duration of action (up to 90 minutes) and cannot be given intravenously. These properties make it less suitable for provision of analgesia in cats because frequent redosing is required.
Morphine is unlicensed in cats, but methadone has received marketing authorisation for administration, making it the opioid of choice when a full µ-agonist with a medium duration of action is required.
In addition to drug licensing, choosing methadone over morphine in cats has a number of other advantages.
Compared to morphine, methadone is less likely to cause nausea and vomiting, so it is preferred in cases where vomiting is contraindicated. Examples of patients for which vomiting is disadvantageous include:
• head trauma patients/neurosurgery (Figure 1) – vomiting causes increased intracranial pressure;
• gastrointestinal disease – for example, animals that are suffering from a foreign body;
• eye surgery – vomiting can increase intraocular pressure;
• neck trauma or cervical disc disease – vomiting might cause neurological derangements due to destabilisation of cervical vertebrae; and
• airway surgery – vomiting may increase the risk of aspiration pneumonia or compromise the surgical site.
Moreover, morphine seems to be less effective in cats compared to dogs, which is hypothesised to be related to cats’ limited production of the active morphine metabolite morphine-6-glucuronide (M-6-G) following administration9.
Similar to all opioids in cats, methadone administration has the potential to cause mild behavioural changes, including excitement, dysphoria and mydriasis. However, these effects are dose-dependent and are less likely to occur when a dose appropriate to the requirement for analgesia is administered. Intravenous dosing during anaesthesia can occasionally result in some respiratory depression (due to a deepening of anaesthesia) and bradycardia. Respiration can be transiently supported by manual ventilation and bradycardia is generally responsive to anticholinergic agents (for example, atropine or glycopyrrolate).
For many types of surgery, particularly when using a multimodal analgesia technique, a single dose of methadone is adequate to provide intraoperative analgesia, but methadone can also be given intraoperatively as a bolus to provide additional analgesia if necessary (Figure 2). If the IV route is chosen, methadone should be injected very slowly to reduce acute cardiovascular and respiratory effects, such as bradycardia, and respiratory depression. Methadone can be given as intermittent boluses in the postoperative period every three to four hours, although some animals may require more frequent dosing.
It is important to emphasise that pain assessment should be performed regularly (at least every two to four hours) in the postoperative period, to titrate pain therapy to the patient’s individual needs and to ensure that adequate pain relief is provided. Pain responses to surgery and injury are unique to each individual, and awareness is increasing that differences in response to opioid therapy in individual animals might reflect genetic variation in such factors as the number, distribution and morphology of opioid receptors.
In conclusion, methadone is a good alternative to other opioid analgesics in cats, especially when moderate to severe pain is expected. Thanks to the recent authorisation of methadone, as well as the increasing knowledge base about the experimental and clinical administration of methadone to cats, feline practitioners might have fewer challenges in the future when managing feline pain.
