Analgesia is a commonly-encountered challenge in equine practice, and a multi-modal approach is often required to provide effective pain relief for horses. There is limited equine-specific research available, so the dosages of analgesic drugs is often extrapolated from research on other species. This article reviews the literature around two analgesic medications commonly used in horses because of their ease of administration, low cost and few perceived side effects.
Paracetamol (acetaminophen)
Paracetamol is one of the most commonly used medications in human medicine. It is an effective anti-pyretic and analgesic agent and is generally considered to have minimal gastrointestinal or renal side effects. Despite its extensive use, the exact mechanisms of action of the drug are not fully understood. Analgesic and anti-inflammatory effects are centrally mediated, possibly via weak prostaglandin inhibition (Graham et al, 2013). Other pathways and possibilities which may be relevant include activation of cannabinoid receptors by the paracetamol metabolite AM404 and activation of the descending serotonergic pathways (Ayoub, 2021). Side effects are rarely reported in humans, although long-term use and overdose can be associated with hepatotoxicity (McCrae et al, 2018). The drug is often used in combination with non-steroidal anti-inflammatory drugs and can have a synergistic effect (Miranda et al, 2006).
Research has evaluated the pharmacokinetics of paracetamol when given orally in horses. The drug is generally rapidly absorbed from the small intestine via passive diffusion. When using a repeated dose of 20 mg/kg, plasma concentrations only reach a level that is considered to be therapeutic in humans for 2 hours (Mercer et al, 2020; Pesko et al, 2022). This dose has been shown to have an effect on thermal nociception in horses for 6 hours (Tueshaus et al, 2023). However, the effective plasma concentration in horses has not been determined. Further studies have evaluated the pharmacokinetics at 30 mg/kg (Mercer et al, 2023a; 2023b), and higher plasma concentrations are achieved at this dose, with plasma concentrations exceeding the suspected analgesic level for 6–8 hours after administration. Bioavailability is variable between horses, which means there are likely to be differences in individual responses; the absolute bioavailability in horses has been estimated to be 91% (Neirinckx et al, 2010). The drug is also highly protein-bound, and this may be important when considering using the drug in horses with low protein levels. Previous studies suggest that there is no significant accumulation of the drug with repeated dosing and the drug appears safe without reported side effects, although the effects of long-term dosing have not been fully evaluated.
The use of paracetamol to treat lameness has also been evaluated, both experimentally and in clinical trials. Paracetamol at an oral dose of 20 or 30 mg/kg was compared with phenylbutazone (2.2 mg/kg) in adult horses with lameness induced by a reversible sole pressure horseshoe model (Mercer et al, 2023a). In this study, horses were administered a single dose of medication 2 hours after induction of lameness. Lameness was evaluated subjectively using a 10-point lameness scale and video analysis. Heart rate was recorded by telemetry. In this study, there was a significant reduction in heart rate in the 30 mg/kg paracetamol group at various time points. Lameness was improved in the 30 mg/kg paracetamol group at 2 and 4 hours, and in the phenylbutazone group at 8 hours. In a similar study, paracetamol at 20 mg/kg was compared with oral flunixin meglumine at 1.1 mg/kg (Foreman et al, 2016). This study reported improvements in heart rate and lameness scores in paracetamol-treated horses, which were similar to those seen in the flunixin-treated horses.
This experimental work has been followed up more recently by a clinical trial in horses with naturally occurring lameness (Mercer et al, 2024). In this study, 12 horses with naturally occurring chronic lameness were treated with paracetamol at a dose of 30 mg/kg twice daily for 21 days. Multiple lameness assessments were made over the study period. Lameness levels were improved at 2 and 4 hours after treatment. Objective lameness locator measurements of lameness improved for up to 8 hours after treatment. Importantly, this study also critically evaluated for adverse side effects. All horses received screening haematology and biochemistry, and either gastroscopy or hepatic ultrasound and biopsy. No significant adverse side effects were noted in any horse.
There are many other potential uses for paracetamol in equine practice, and it is an attractive option in horses with systemic illness in which other medications, such as non-steroidal anti-inflammatory drugs, may be contraindicated. Paracetamol, at a dose of 30 mg/kg, has been evaluated in adult horses with experimentally-induced endotoxaemia, and compared to flunixin meglumine (Mercer et al, 2023b). In this study, a significant reduction in heart rate and body temperature was seen at 4 and 6 hours after treatment, although a greater effect was observed in the flunixin-treated horses. The pharmacokinetics were also slightly different, with a lower maximum plasma concentration than reported in healthy horses. This may be related to a delay in gastric emptying caused by endotoxaemia. Paracetamol has also been shown to penetrate readily into the aqueous humour of the eye (Peraza et al, 2023), suggesting that the medication is also likely to have a clinical use for the treatment of ocular pain in horses.
Paracetamol is commonly used in human neonates and a number of studies have evaluated the pharmacokinetics in healthy foals (Faivre et al, 2023; Gold et al, 2023a; 2023b). The desired therapeutic concentration is unknown in foals, and these studies suggest that the pharmacokinetics of the drug alter with foal age. The drug is rapidly absorbed in foals, and no significant adverse effects were reported, with the exception of some minor changes in tissue enzyme concentrations, including blood urea nitrogen and serum alkaline phosphatase, which were clinically insignificant. These studies suggest that a higher dose of 40 mg/kg may be needed in foals to achieve maximum therapeutic benefit, but further research is needed to confirm this.
Paracetamol summary
Overall, these studies offer reasonable quality evidence to support the use of paracetamol in equine practice. In horses without systemic disease, a dose of 30 mg/kg is likely to achieve effective plasma concentrations. In foals or horses with systemic disease, more research is needed to establish the most effective dose. However, a dose of 30 mg/kg is likely to be safe in adult horses, and doses of 40–60 mg/kg have not been associated with adverse effects in foals. One of the major limitations of the use of the medication as a sole analgesic agent is its duration of effect. Clinical effect is probably limited to 4–8 hours after treatment. This means that in many situations, the drug should be used in combination with other analgesic drugs to provide more balanced, multi-modal analgesia. The use of paracetamol as part of a multi-modal regimen has been described in a horse with pelvic limb compartment syndrome (Bruniges et al, 2019) and a pony with laminitis (West et al, 2011). Further evaluation is required to assess whether dosing every 8 hours would be appropriate and to assess the safety of longer term use of the drug.
Gabapentin
Gabapentin is an anticonvulsant medication used to treat a number of conditions in human medicine, including seizures and neuropathic pain (Di Cesare et al, 2023). Gabapentin is a gamma-aminobutyric acid analogue which is thought to act via voltage-gated calcium channels in the central nervous system, although its exact mechanism of action in the central nervous system is not fully understood (Terry et al, 2010).
Gabapentin has poor oral bioavailability in the horse; it is estimated to be about 16% (Di Cesare et al, 2023), which is lower than in other species. The therapeutic plasma concentration in horses is unknown. However, if therapeutic levels are similar in horses and humans, higher doses are likely to be required. Early reports of the use of gabapentin in horses used low doses of 2.5–5 mg/kg orally twice daily with reported benefit (Davis et al, 2007; Caldwell et al, 2015). These doses are unlikely to achieve effective therapeutic concentrations. Previous studies have suggested that a dose of 20 mg/kg twice daily is more likely to be effective (Gold et al, 2020). However, the relationship between dose and absorption is not linear, and much higher doses (up to 120 mg/kg) may be needed to reach therapeutic concentrations (Gold et al, 2022). In humans, reported side effects include somnolence, ataxia, dizziness and, more rarely, renal failure and cardiovascular and renal complications (Rose and Kam, 2002). Significant side effects have not been reported at any dose in the horse and the medication appears safe.
Two studies have evaluated the use of gabapentin in horses with chronic thoracic limb lameness at varied doses (5 and 10 mg/kg three times daily, and 20 mg/kg twice daily) (Caldwell et al, 2015; Young et al, 2020). Neither study showed any significant effect on lameness either subjectively or using force plate analysis. Lameness was improved in horses receiving gabapentin and firocoxib combined (Young et al, 2020). However, the improvement was not significantly greater than when using firocoxib alone. These studies suggest that there is no clinical evidence to support the use of gabapentin for chronic musculoskeletal pain.
The most suitable use for gabapentin in the horse is for cases experiencing neuropathic pain. However, the ability to detect and quantify neuropathic pain in the horse is very limited, which makes evaluation of efficacy difficult. The quality of the evidence supporting the use of gabapentin for neuropathic problems is consequently poor and consists predominantly of individual case reports. The use of low dose of gabapentin (2.5 mg/kg) is described in a pregnant large breed mare suffering from intractable pelvic limb pain following colic surgery. In this case, it was reported that clinical signs resolved shortly after the addition of gabapentin as part of a multi-modal analgesic regimen (Davis et al, 2007). Based on pharmacokinetic studies, the plasma levels in this horse were likely to have been very low, raising the question as to whether the improvement was truly related to gabapentin or not. A single horse with severe headshaking as a result of temporohyoid osteoarthropathy was reported to have resolution of headshaking following treatment with gabapentin at 5 mg/kg twice daily (Readford et al, 2013). In a larger case series of horses with ‘hopping lameness’ as a result of suspected cervical pain (Dyson and Rasotto, 2016), two of four horses treated with gabapentin at 5 mg/kg were reported to have a significant improvement in clinical signs. Further work is needed to understand the true clinical indications for the use of gabapentin and the most effective dosing regimens.
Pregabalin is a similar gamma-aminobutyric acid analogue to gabapentin but with greater bioavailability and receptor affinity in humans. A single pharmacokinetic study has suggested that the medication has better bioavailability in the horse, with the potential to reach therapeutic concentrations at reasonable doses (Mullen et al, 2013). This medication may be more suitable for the treatment of neuropathic pain in the horse. A further study has evaluated the potential use of this medication as part of a sedative protocol (Shokrollahi et al, 2024).
Gabapentin summary
The current available evidence supporting the use of gabapentin is limited. There is no evidence to suggest that gabapentin has a beneficial effect in horses with chronic musculoskeletal pain. There is some evidence to support the use of gabapentin in horses with neuropathic pain, but further work is needed to establish the correct dose.
Conclusions
There is evidence to support the use of paracetamol at a dose of 30 mg/kg in equine practice, but further research is needed to confirm the most effective dose for foals and horses with systemic disease. The analgesic effect of the drug is limited to 4–8 hours after treatment, so it should be used alongside other drugs to maintain balanced analgesia. The evidence for gabapentin is limited – there is evidence that is can be effective in horses with neuropathic pain, but no evidence to support its use in horses with musculoskeletal pain. Further research is required to establish the effective dose of this drug.