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

a Knowledge Summary by

Theophanes Liatis DVM (Hons) MRCVS ^1*

¹Small Animal Hospital, University of Glasgow, 464 Bearsden Rd, Bearsden, Glasgow G61 1BD
^*Corresponding Author (theofanis.liatis@gmail.com)

The term tremor used throughout the paper has been more recently replaced by the term twitches which is acknowledged by the author (Lowrie & Garosi, 2016).

Clinical scenario

A 4-year-old male neutered dog is presented to you as an emergency due to acute ongoing generalised muscle tremors. Prior to the episode, the dog was out for a walk at the neighborhood. Physical examination reveals hyperthermia (40.5^oC), neurological examination reveals generalised muscle tremors, however the dog is bright, alert and responsive. Based on generalised muscle tremors and absence of other neurological findings, you suspect that the hyperthermia is secondary to the tremors, and you neurolocalise forebrain, cerebellum, meninges (pyrexia), peripheral nerve or multifocal, as it is difficult to clinically establish the origin of  generalised muscle tremors. You observe some watery discharge of blue/green colour from the anus, compatible with the colour of the commercial form of slug bait, and thus you suspect metaldehyde intoxication. Would you choose methocarbamol or benzodiazepines to relax the muscles and reduce the tremors of the dog?

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

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; and Van Tulder et al., 2003). Benzodiazepines are quite beneficial as most of them can be administered through different routes (intravenous [IV], intramuscular [IM], per os [PO], intranasal [IN], intrarectal [IR]) (Podell, 1995; and Charalambous et al., 2017). Diazepam reaches therapeutic plasma levels within 10 minutes when administered IN or IV (Musulin et al., 2011) or IR (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). As a take-home medication, recently, midazolam IN revealed to be superior to diazepam IR for status epilepticus (Charalambous et al., 2017). Midazolam’s major drawbacks include: (a) dose-dependence on plasma protein concentrations (as it is protein binding); (b) shorter serum half-life (within almost an hour) compared to diazepam, and therefore necessity for a CRI; and (c) respiratory depression when used with other narcotics (e.g. opioids) (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. (2007) described cases of metaldehyde intoxication treated with benzodiazepines, most of which were accompanied by barbiturates (phenobarbital or pentobarbital). Due to the administration of the above mentioned antiepileptic drugs, no conclusion can be made about the diazepam only efficacy to these patients, whilst no case with methocarbamol treatment is described. Zimmerman et al. (2010) treated all three metaldehyde intoxication cases with diazepam followed by barbiturates amongst other medications, with an aim to control the status epilepticus. All cases recovered, however due to the multimodal nature of treatment, no conclusion could be made for the diazepam only efficacy. Jull et al. (2011) described similar therapeutic protocols.

Bates et al. (2012) described that general practitioners preference to use of benzodiazepines (392/772 cases) among other treatment protocols as either monotherapy or multimodal therapy, with barbiturates being used frequently (227/772 cases). Only 2/772 cases were reported to have used methocarbamol in the therapeutic protocol.

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; Yas-Natan et al., 2007; Zimmermann et al., 2010; Jull et al., 2011; and Bates et al., 2012). 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.

Methodology Section

Search Strategy
Databases searched and dates covered:	CAB Abstracts, 1973 to 2019 week 25 PubMed, 1966 to current
Search strategy:	CAB Abstracts: (dog OR dogs OR canine OR canines OR canis OR bitch OR bitches OR puppy OR puppies OR pup OR pups) OR exp dogs/ OR exp bitches/ OR exp puppies/ OR exp canidae/ OR exp canis/ metaldehyde.mp. OR exp metaldehyde/ OR 'slug bait'.mp. OR tremorgenic (intoxication OR toxic* OR poison* OR toxicosis) OR exp toxicity/ OR exp poisoning/ 1 AND 2 AND 3   PubMed: dog OR dogs OR canine OR canines OR canis OR bitch OR bitches OR  puppy OR puppies OR pup OR pups metaldehyde OR slug bait OR tremorgenic intoxication OR toxic* OR poison* OR toxicosis 1 AND 2 AND 3
Dates searches performed:	2 July 2019

Exclusion / Inclusion Criteria
Exclusion:	Articles not available in English, articles which were not relevant to the PICO question. book chapters, literature reviews, single case reports, conference proceedings
Inclusion:	Original peer-reviewed articles in English language with more than one dog intoxicated by metaldehyde and treated with benzodiazepines and/or methocarbamol

Search Outcome
Database	Number of results	Excluded – non-English Language	Excluded – not relevant with the PICO	Excluded – book chapters	Excluded – reviews	Excluded – case reports	Excluded – conference proceedings	Total relevant papers
CAB Abstracts	113	16	71	2	11	5	3	5
PubMed	52	0	36	0	10	1	0	5
Total relevant papers when duplicates removed								5

The author declares no conflicts of interest.

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