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Evaluating delivery of high doses of buprenorphine for pain

Taylor PM, Luangdilok CH, Sear JW. Pharmacokinetic and pharmacodynamic evaluation of high doses of buprenorphine delivered via high-concentration formulations in cats. J Feline Med Surg. 2016 Apr;18(4):290-302. 

Pain management in cats is a crucial part of modern veterinary medicine. Cats who are fee of pain experience faster healing, better appetites, and improved qualities of life. There are many options for pain management available, including anti-inflammatories, local anaesthetics, novel therapies such as gabapentin and amantadine, and alternative modalities such as acupuncture and laser therapy. However, as in humans, opioids remain a mainstay of pain control due to their rapid onset of action, profound analgesia, and minimal physiologic side effects.

Buprenorphine has become one of the most commonly used medications for feline analgesia in recent years for a variety of reasons. It is capable of providing moderate to marked pain control with a 6 to 8 hours duration of action, and causes minimal sedation and no cardiovascular depression. It may be administered by intramuscular, intravenous, or oral trans-mucosal routes, facilitating administration. Administering medications to a cat can be challenging, however, and so maximizing the duration of action of medications is ideal. There have also been recent concerns regarding the efficacy and bioavailability of oral trans mucosal administration of buprenorphine.

While SQ administration of buprenorphine has long be considered not to reach analgesic efficacy, recent commercial products have entered the market claiming 24h duration of analgesia with SQ administration, at a much higher dose than generally given through other routes. While slow-release compounds have been available on the market, they have increased cost and are more difficult to inject compared to standard aqueous formulations. High dose buprenorphine has previously been shown to be safe in cats, this study attempted to determine its duration and efficacy.

12 healthy adult cats were included in this study, which included 12 different serial or crossover studies designed to evaluate 8 variations in buprenorphine formulation and dose. Analgesic efficacy was determined by thermal threshold, a methodology whereby a heated probe is held against a small area of shaved skin with constant pressure and the temperature slowly increased until signs of discomfort (skin flick, biting the probe, vocalization, etc) were seen. Blood concentrations of buprenorphine were also determined and pharmacokinetic and pharmacodynamic calculations completed.

Cats were administered standard (0.02mg/kg), medium (0.06mg/kg), high (0.12mg/kg) or very high (0.24mg/kg) doses of buprenorphine, or control (5% dextrose in water). Various concentrations of drug were also tested.

Cats at all doses had significant changes to thermal threshold at some point in the study compared to baseline and placebo. Maximum thermal threshold was the same regardless of the dose of drug used. Time to onset was consistently ~1h in all cats.

Duration of action, however, was seen to be dependent on the dose of buprenorphine used. Both pharmacokinetic assays and thermal threshold values indicated that standard doses of buprenorphine (0.02mg/kg) led to analgesia for a period of 6-12h. The higher doses had durations of action consistently over 24h and often approaching 48. No significant difference was found in the duration of action between medium, high, and very high dosages, however drug metabolites such as norbuprenorphine were detected in cats at the high and very high dosages.

The only side effect found in this study was the presence of mydriasis (pupil dilation), a very minor concern.

Unsurprisingly, dose was not seen to be a factor in the strength of analgesia obtained. As a complex partial agonist this is not surprising, as drugs of this type are well known to have a “ceiling” effect after which further strength of analgesia is not obtained.

There were several limitations to this study. Thermal threshold pain is not the same as the pain encountered in a clinical setting, and this must be taken into account. The number of cats in this study was too small for full statistical analysis. Some of the results (such as the efficacy of 0.02mg/kg SQ buprenorphine) have some confliction with other studies, though the authors agree that this dosage and route should likely be avoided.

Despite the limitations this paper convincingly demonstrates that SQ administration of high doses (0.12-0.24mg/kg) of buprenorphine is a safe and effective way to achieve 24-48 hours of pain control in cats. Further work should be done to investigate the utility of this method of administration in a clinical context. (MRK)

See also:
Taylor PM, Kirby JJ, Robinson C, et al. A prospective multi- centre clinical trial to compare buprenorphine and butorphanol for postoperative analgesia in cats. J Feline Med Surg 2010; 12: 247–255.

Catbagan DL, Quimby JM, Mama KR, et al. Comparison of the efficacy and adverse effects of sustained-release buprenorphine hydrochloride following subcutaneous administration and buprenorphine hydrochloride following oral transmucosal administration in cats undergoing ovariohysterectomy. Am J Vet Res 2011; 72: 461–466.