Methocarbamol CRI for Symptomatic Treatment of Pyrethroid Intoxication: A Report of Three Cases

Introduction

Pyrethrum is a combination of six natural insecticidal esters called pyrethrins. Pyrethrins are naturally occurring compounds derived from a combination of insecticidal esters (pyrethrins, cinerins, and jasmolins) that are isolated from the flowers of Chrysanthemum cinerariaefolium and related species.^1,2 Pyrethrins are poisons that act on the nervous system. Products containing 45–65% permethrin intended for use in dogs only are particularly concerning. Pets may be adversely affected after either oral ingestion or by topical application of such concentrated products.^1,3,4

The clinical signs most commonly reported with pyrethroid toxicity in the veterinary literature include hypersalivation, muscle tremors/fasciculations, hyperthermia, hyperesthesia, ataxia, hyperexcitability, mydriasis, and seizures.^3,5–8 The onset of clinical signs is usually within a few hr of exposure, with some being delayed for up to 72 hr postexposure.^3,7,9 Symptomatic treatment regimens are based on control of the muscle tremors and/or seizures, supportive care, and decontamination.^5,10 Traditionally, it is recommended to control the muscle tremors with IV boluses of methocarbamol, a centrally acting muscle relaxant, and to treat seizures with IV diazepam and/or barbiturates.

In this report, three cases of pyrethroid toxicity successfully treated with methocarbamol using a continuous rate infusion (CRI) technique are described. To the authors’ knowledge, there have not been any studies previously published regarding the use of a methocarbamol CRI in animals presenting with pyrethroid intoxication.

Case Report

The two cats described in the following section were treated at the College of Veterinary Medicine, University of Illinois between February 2009 and March 2009. The dog described below presented in June 2010 to the University of Florida’s College of Veterinary Medicine. Before transfer to the authors' institution and/or clinical service all three animals were treated with diazepam, and two of them were treated with phenobarbital. Both of those treatments achieved only minimal control of muscle tremors. All three patients responded well to methocarbamol IV boluses, and a complete resolution of muscle tremors was achieved after starting a methocarbamol CRI.

Case 1

A 3 yr old castrated male domestic shorthair weighing 5.6 kg presented to the University of Illinois Veterinary Teaching Hospital in lateral recumbency and with severe, generalized, muscle tremors after being found in a ditch by the owners’ neighbors in the morning. The neighbors were not able to contact the owners at the time of presentation to collect more information about the cat’s history. On physical examination, a mild tachypnea was noted. Due to the severity of the muscle tremors, a full neurologic examination and evaluation for appropriate mentation were not possible. The remaining vital parameters were within normal limits (Table 1). Given the clinical presentation and inability to obtain additional historic information, seizures and possible head trauma were initially suspected. An IV catheter was placed, and the cat was treated with IV diazepam^a (1 mg/kg) followed by phenobarbital^b (6 mg/kg IV), which did not reduce the clinical signs. The cat was administered 25% mannitol^c (10 mL IV slowly over 20 min) and was maintained on flow-by oxygen at 2 L/min via a face mask. A packed cell volume, total plasma protein, and blood gas analysis^d was performed, and no major abnormalities were identified (Table 1). The owners were eventually contacted, and they stated that the cat was healthy and normal before they left for work that morning. Because of a flea infestation, the owners had applied their dog’s flea prevention, which contained imidacloprid (8.8%), permethrin (44.0%), and pyripoxyfen^e (0.44%), on the cat early that morning. Based on that information, the cat was then bathed with soap and given an IV bolus of methocarbamol^f at a dose of 89.3 mg/kg. The tremors were reduced shortly after that treatment. The cat was then placed on IV lactated Ringer’s solution^g (2.7 mL/kg/hr) and a methocarbamol CRI (8.8 mg/kg/hr). After a few hr, the muscle tremors had ceased. After 8 hr, the methocarbamol CRI was decreased to 4.7 mg/kg/hr for an additional 4 hr, and minimal tremors were noted. The cat was discharged on the same day with minimal tremors and was prescribed methocarbamol (45 mg/kg per os [PO] q 8 hr for 2 days). No muscle tremors were present at a follow-up appointment 3 days after discharge.

TABLE 1 Summary of Vital Parameters and Blood Work in the Three Described Cases

*

Reference ranges and units are provided in parentheses.

BUN, blood urea nitrogen; Cl, chloride; iCa; ionized Ca; K, potassium; N/A, not available; PCV, packed cell volume; TS, total solids.

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Discussion

This case series documents the use of methocarbamol as a CRI for control of muscle tremors due to pyrethroid toxicosis in two cats and one dog. The prognosis for recovery from intoxication due to pyrethroids is good, presuming therapy is instituted early in the course of the disease. The majority of animals that receive prompt and aggressive treatment recover within 48–72 hr with few permanent sequelae.^1,2,5,9

Methocarbamol is a propanediol, and this class of drug has its therapeutic value in abolishing abnormal muscle tone and involuntary movement without impairing normal neuromuscular function. Methocarbamol has a greater effect in the spinal cord compared with the brain. This is displayed in its ability to protect against the convulsant effects of strychnine (a spinal cord stimulant), but not pentylenetetrazol (a stimulant that produces excitation in the central nervous system rostral to the foramen magnum).¹¹ Methocarbamol, given as intermittent injections, is often a first-line treatment for the control of increased muscular activity associated with pyrethroid intoxication.^1,5,10 To the authors’ knowledge, methocarbamol has not been used as a CRI in humans, dogs, or cats; therefore, specific information regarding pharmacodynamics and pharmacokinetics of a CRI are lacking at this point. At clinically relevant doses, methocarbamol reportedly prolongs the refractory period of skeletal muscle by a direct action on the fibers.¹² That same study showed that diazepam did not have that direct effect on the muscles.¹² That additional mechanism could also be helpful in controlling the spasms related to pyrethroid intoxication.

The dose of methocarbamol used by the authors was based on the published maximum safe dose of 330 mg/kg/day. The initial bolus of methocarbamol administered to the patient was subtracted from the total daily dose, and the remainder was administered as a CRI. The CRI can be administered either as the drug alone on a syringe pump (as described in case 3) or as the drug added to a fluid bag (e.g., methocarbamol added to 240 mL of 0.9% NaCl) and given as a CRI (10 mL/hr to start, then tapered as necessary) as described in cases 1 and 2. The decision of when to taper, and by how much, is dependent on the clinician and patient. The decision to use a CRI instead of multiple boluses is made for a number of reasons, including reduced stress on the patient (because the tremors rarely return), reduced need for the ICU staff to monitor for recurrence of tremors, and the routine need for less total medication when given as a CRI.

Methocarbamol, given intermittently, is often considered a first-line treatment of muscle tremors due to pyrethroid intoxication. Although seizures are rarely a sequela of pyrethroid intoxication (and can be difficult to differentiate from severe tremors), a wide variety of pharmacologic treatments have been reported, including intermittent boluses of diazepam and phenobarbital. Those drugs are sometimes followed by a CRI of either a benzodiazepine (i.e., diazepam, midazolam) or propofol. Given a lack of historical information at the time of presentation for case 1, the authors suspected seizures and possible head trauma. After collecting additional information, treatment with methocarbamol was initiated, which controlled the muscle tremors when administered as an IV bolus followed by a CRI. In retrospect, all three of the cases should have been treated with a methocarbamol bolus followed by a CRI immediately after presentation. It is likely that this would have controlled any tremors due to the pyrethroid intoxication, obviating the need for other medications with more side effects.⁶

General supportive care for pyrethroid intoxication was provided for all three cases described in this report, including bathing the animals in a dilute solution of liquid dishwashing detergent to help remove residual drug from the skin and coat, maintenance of normothermia, IV fluid therapy to support circulation, and monitoring in the ICU.

In this small case series, there did not appear to be any side effects associated with using a methocarbamol CRI, and all three patients had resolution of clinical signs. Because all three patients were treated with diazepam and/or phenobarbital, it is not entirely clear that the resolution was due to methocarbamol alone. When giving IV boluses of methocarbamol, the muscle tremors should become less intense but the action appears to be short lived. To avoid using multiple drugs that can cause side effects and promote little muscle relaxation effect (as was performed in the three cases described herein), a CRI of methocarbamol should be started immediately after the IV bolus. As described above, the methocarbamol CRIs were not initiated without an initial IV bolus.

Conclusion

The use of methocarbamol as a CRI for pyrethroid intoxication appeared beneficial in this report; however, further studies regarding the pharmacology of methocarbamol (in general and as a CRI) and to examine the efficacy of methocarbamol for tremorogenic diseases are necessary.