In dogs with metaldehyde intoxication, are benzodiazepines more effective than methocarbamol in relaxing muscles and reducing tremors?

acting (b) the patient stress factor: no oral or and safety of the staff: is that could administration oral muscle tremors


The evidence
Five studies of indirect relevance to the PICO were reviewed, all of them being retrospective in nature. Due to a lack of prospective or retrospective studies with direct correlation of benzodiazepines and methocarbamol treatment without administration of other medications (e.g. antiepileptic drugs), the strength of the evidence is extremely low.

Summary of the evidence 1. Firth (1992)
Population: Dogs with snail bait poisoning (metaldehyde or methiocarb) and follow-up. This study was conducted in Australia

Sample size: 56 dogs
Intervention details:  26/56 dogs were intoxicated by metaldehyde (30/56 dogs were intoxicated by methiocarb)  There is no information whether the intoxicated dogs manifested epileptic seizures, tremors or both  There is no information whether the dogs were amenable or not to administration of oral medications upon presentation  Treatment was achieved with sedatives, general anaesthetics and/or muscle relaxants including: a. diazepam premedication (9/26) b. diazepam/ketamine general anaesthesia (GA) (12/26) c. diazepam/ketamine/lidocaine GA (7/26) d. lidocaine/ketamine GA (1/26) e. methocarbamol (post-GA) (6/26)  Methocarbamol was given only after performing GA with either one of the above mentioned GA protocols, but not as sole medication  Two dogs were lost to follow-up Study design: Retrospective, single centre, case series Outcome studied:  Different management protocols (including the use of premedication, general anaesthesia and post-general anaesthesia relaxants)  The correlation between the treatment modality and patients' response and outcome There was full recovery of 100% (24/24) metaldehyde intoxication cases using multimodal treatment, most of which included diazepam. However, there was no comparison between the usage of benzodiazepines and methocarbamol

Limitations:
 This is a retrospective, single centre, case series study with a low level of evidence.  The usage of methocarbamol was additional to a GA protocol that might or might not include diazepam  The outcome was not correlated with the specific treatment that each dog had  Dogs with metaldehyde intoxication which were treated with benzodiazepine monotherapy (diazepam or midazolam) survived and did not manifest any post intoxication seizures  3/17 dogs of the metaldehyde intoxication group were discharged with oral antiepileptic treatment (phenobarbital) which was tapered gradually until discontinuation  Median follow-up time for the 20 dogs was 757 days. The 17 dogs with metaldehyde intoxication survived and none of them manifested any post intoxication seizures  All metaldehyde intoxicated dogs survived

Limitations:
 This is a retrospective, multi-centre, case series study with a low level of evidence  The multi-center nature of the study increases the possibility of non-standardised protocols between the centres, and thus the strength of the study  There was no case treated with methocarbamol  Due to the nature of the study, no direct comparison between the different treatments can be reliably assumed  Benzodiazepines remain a major option for metaldehyde intoxication treatment for the 50% of the cases, however there is evidence that refractory cases require further medications/anaesthetics  The use of barbiturates and benzodiazepines remained fairly constant over the period examined  Benzodiazepines were given to half the dogs in this cases series  Methocarbamol was used only in two cases most likely as a result of the decreased availability in the UK

Limitations:
 This is a retrospective, multi-centre, case series study with a low level of evidence  The multi-centre and questionnaire based nature of the study increases the possibility of non-standardised protocols between the centres, and thus the strength of the study  There were only two cases treated with methocarbamol, with no detailed reference as to the outcome  The outcome was not correlated with the specific treatment that each dog had, making any evaluation of the benzodiazepine or methocarbamol efficacy to each case impossible

Appraisal, application and reflection
Metaldehyde intoxication is a common intoxication in dogs attributed to ingestion of slug bait, which consists of the carbamate named metaldehyde. Clinical signs include generalised muscle tremors and/or epileptic seizures, as well as a variety of other signs (Dolder, 2003). Among others (e.g. metabolic acidosis), one of the major causes of death in such cases is the hyperthermia secondary to the excessive generalised muscle tremors (Dolder, 2003). Consequently, one of the major therapeutic goals of the general practitioner is to decrease the muscle tremors, avoiding hyperthermia. As mentioned already, there are no prospective or retrospective studies in the literature to compare different treatments for metaldehyde intoxication in dogs focusing on benzodiazepines and methocarbamol. Benzodiazepines bind to γ-aminobutyric acid (GABA) receptors of the brain resulting in increased GABA activity, which is the main neurotransmitter of the brain. Consequently, they are used as centrally acting skeletal muscle relaxants, but also as anxiolytics, sedatives, hypnotics and anticonvulsants (Podell, 1995 (Papich & Alcorn, 2007) or 30 minutes to 2 hours when administered PO (Plumb, 2008). Diazepam IM has a slower and incomplete absorption (Plumb, 2008). The serum half-life of diazepam in dogs is 2.5-3.2 hours (Plumb, 2008). Diazepam's major drawbacks include: (a) possible cause of contradictory response (central nervous system excitement) (Plumb, 2008); (b) sedative inefficacy (Plumb, 2008); (c) tolerance to its anticonvulsant effect in dogs (Frey et al., 1984); and (d) inability to administer as a constant-rate infusion (CRI) solution as its availability might be reduced within the plastic syringe (Cloyd et al., 1980). Midazolam's unique solubility characteristics (water soluble injection but with high lipophilicity at body pH) give it a very rapid onset of action after injection (Plumb, 2008). Although midazolam IV provides the quickest onset of action (Plumb, 2008), IN route provides superiority when the time needed to place an IV catheter is taken into account and same efficacy (Charalambous et al., 2019). Midazolam IM is rapidly and completely absorbed, in contrast with diazepam IM. Midazolam PO is not commercially available, whilst midazolam IR is not clinically useful due to very low rectal bioavailability. Compared to diazepam, midazolam is nearly 3 times as potent, and has a faster onset of action (in humans 30-97 seconds), but a shorter duration of effect. Midazolam can also provide sedation if used with opioids, in contrast to diazepam (Plumb, 2008 Methocarbamol is a centrally acting muscle relaxant that selectively blocks polysynaptic reflex pathways in the spinal cord without any effect on monosynaptic pathways, whilst it has no direct effect on the contractile mechanism of the striated muscle, the nerve fibre or the motor end plate (Van Tulder et al., 2003;and Nielsen et al., 2005). It has been used in veterinary medicine in traumatic myopathies or intoxications (including tetanus) (Nielsen et al., 2005). Oral tablets are the only commercially available form of methocarbamol, although it can be prepared in an off-label enema in hospital. Methocarbamol has an onset of action of about 30 minutes after oral administration. Its peak levels in humans occur approximately 2 hours after dosing, and its serum half-life is about 1-2 hours (Plumb, 2008). In the US, methocarbamol IV is available as well, and successful management of tremors has been reported with methocarbamol CRI in cats (Draper et al., 2013). Methocarbamol's major drawbacks include: (a) limited routes of administration in combination with availability limited to the oral form in Europe; (b) delayed onset of action compared to benzodiazepines IV; and (c) central nervous system depressant effects as a carbamate (sedation, salivation, lethargy, weakness, ataxia) (Plumb, 2008).
Most of the above mentioned retrospective studies include benzodiazepines and particularly diazepam as one of the most common first-line drugs for the treatment of metaldehyde intoxication. Firth (1992) reported metaldehyde intoxicated dogs treated with diazepam or methocarbamol. Both canine groups were treated with diazepam or methocarbamol as a part of a multimodal treatment which included additionally a general anaesthetic. All dogs recovered, but no comparison between the groups can be made for the efficacy of either diazepam or methocarbamol. Yas-Natan et al. In practice, the vast majority of dogs suspected to be intoxicated by metaldehyde are presented with epileptic seizures (e.g. status epilepticus) and/or generalised muscle tremors. At the time of presentation, the general practitioner is not able to distinguish the origin of the clinical signs, and given the emergency nature of these cases, injectable benzodiazepines (and specifically diazepam) are the first choice. Injectable benzodiazepines offer rapid onset of action and have both antiepileptic and muscle relaxant properties. Additionally, both generalised muscle tremors and epileptic seizures usually include motor activity of the facial and masticatory muscles and thus jaw movements, which makes any oral administration unsafe for the veterinary surgeon. Therefore, these reasons, as well as the restricted administration routes of methocarbamol, could probably explain why the vast majority of studies include primarily benzodiazepines rather than methocarbamol.

Conclusions
In conclusion, there is not enough evidence to define whether benzodiazepines (e.g. diazepam, midazolam) or methocarbamol is better for the control of muscle tremors during metaldehyde intoxication, thus the answer of the current PICO remains open. Although it is reported that the availability of methocarbamol is limited in the UK (Bates et al., 2012) and there are no prospective studies describing its efficacy on tremors, it is suggested that methocarbamol is very successful in reducing muscle tremors during this intoxication (Dolder, 2003). Due to possible manifestation of epileptic seizures concurrently with the generalised muscle tremors and in the light of their anticonvulsant activity, their broader availability, their multiple administration routes and their rapid action when given IV, benzodiazepines are preferred for the initiation of the treatment in cases of metaldehyde intoxication by many vets; and they carry on with an antiepileptic drug (e.g. phenobarbital) or general anaesthesia (Firth, 1992 It is important to note that in the decision-making process, apart from the pharmacological features of each medication, all points of care should be taken into consideration such as: (a) best practice: each patient should be treated with the best practice that would be to treat the dog immediately with the faster acting drug; (b) the patient stress factor: that is no oral medications should be administered in a patient with risk of regurgitation or distress; and (c) safety of the staff: that is risks that could arise from administration of oral medications in a dog with generalised muscle tremors (including the jaw). Further studies are necessary to provide information on the efficacy of benzodiazepines or methocarbamol in patients with metaldehyde intoxication.