A 6-year-old 28.5-kg (62.7-lb) spayed female Boxer was evaluated at the North Carolina State University VTH for surgical repair of a ruptured cranial cruciate ligament. History was unremarkable (including no previous problems with anesthesia), and results of physical examination and routine clinicopathologic analyses were within reference limits. After food was withheld for 12 hours, the dog received IM injections of hydromorphone (0.1 mg/kg [0.045 mg/lb]) and medetomidine (8 μg/kg [3.64 μg/lb]). Anesthesia was induced with 3 mg/ kg (1.36 mg/lb) of propofol administered IV and maintained with isoflurane in oxygen to effect. Physiologic measurements were initially obtained via continuous ECG monitoring, capnography, and intermittent indirect oscillometric blood pressurea (for which continuous direct arterial blood pressure monitoringa was later substituted). The anesthetic plan included a caudal epidural injection of preservative-free morphine sulfateb (0.1 mg/kg) in combination with bupivacaine hydrochloride (1 mg/kg [0.45 mg/lb]). During placement of the epidural needle into the epidural space, CSF was detected in the needle, indicating subarachnoid placement. For subarachnoid injections, the convention in effect at the VTH at that time was to administer only morphine at a dose 50% less than that used for epidural injections (ie, 0.05 mg/kg [0.02 mg/lb]). The concentration of the preparation of preservative-free morphine typically used in the VTH was 1 mg/mL.b Inadvertently, the morphine preparation used in the injection administered to the dog had a concentration of 25 mg/mL.c Thus, instead of a subarachnoid injection of morphine at a dose of 0.05 mg/kg, the dog received a subarachnoid injection at a dose of 1.3 mg/kg (0.59 mg/lb), which was 26 times greater than the dose appropriate for this route of administration.
In the small animal section of the VTH, controlled drugs were dispensed from a password-controlled automated drug-dispensing machine, which was accessible to veterinarians every hour of every day. Single vials or ampules of drugs were dispensed pursuant to correct entry of information including an identification number of the ordering veterinarian, password, patient number and name, and drug required. There were 5 different formulations and concentrations of morphine in the drug-dispensing machine: morphine sulfate (concentration, 15 mg/mL [volumes of 1 and 20 mL]), preservative-free morphine sulfate (concentrations of 1 mg/ mL [volume, 10 mL] and 25 mg/mL [volume, 10 mL]), and a 1% topical solution of morphine sulfate (volume, 1 mL). Each vial was stacked in a separate column and keyed to a specific key on the drug machine keyboard to ensure that the drug dispensed exactly matched the keyboard selection made by the user. The preparation of morphine dispensed by the automated machine was not checked by the user prior to administration to the dog.
Because intrathecal overdose of morphine in dogs had not been described in the veterinary literature to our knowledge, no treatment was instituted and the dog was monitored for adverse effects. Approximately 50 minutes after subarachnoid injection and prior to the start of the surgical procedure, mild focal myoclonic contractions were detected at the level of the dog's tail. The duration of each contraction was 1 to 2 seconds, and they occurred spontaneously every 5 to 10 minutes or after local pressure stimulation. During this time, the dog's level of anesthesia was assessed as being at an adequate surgical plane, and the contractions were diagnosed as myoclonic movements. Surgery began approximately 1 hour after the injection, and the stimulus of surgery did not appear to affect the frequency or intensity of the myoclonic activity. Midazolam (0.1 mg/ kg) was administered IV and was somewhat effective in inducing muscle relaxation, decreasing the severity of the contractions, and prolonging the interval between spasms. However, during the following 30 minutes, the myoclonic movements increased in intensity and frequency and began to develop in more cranial regions. At 120 minutes after the injection, myoclonia was evident at the level of the hind limbs. Midazolam treatment (at the same dose) was repeated 3 times at 5-minute intervals, but the spasms were refractory to treatment. Neuromuscular blockade was instituted with administration of multiple boluses of atracurium (0.1 mg/kg, IV) and was effective in diminishing the intensity and frequency of the myoclonic movements. Positive pressure ventilation was simultaneously instituted.
The surgical procedure was completed successfully within approximately 2 hours, after which time the dog (still anesthetized) was transferred into another area for monitoring and treatment of the myoclonus. Approximately 4.5 hours after administration of the morphine overdose, the myoclonic movements worsened. Multiple boluses of naloxone hydrochloride (0.8 mg, IV) were administered without effect. Phenobarbital sodium (2.25 mg/kg [1.02 mg/lb]) and pentobarbital sodium (2.08 mg/kg [0.95 mg/lb]) were administered IV in response to the severity of the myoclonic movements and to evaluate whether any component of the spasms was possibly seizure activity. Neither drug was effective in achieving complete relaxation of the dog or stopping the myoclonic movements; thus, the decision was made to transfer the dog to the intensive care unit for further treatment.
The dog was admitted to the intensive care unit at approximately 5 hours after the overdose. Continued treatment attempts with midazolam, pentobarbital, and naloxone failed to control the myoclonus; myoclonic activity worsened, and hyperthermia (41.6°C [107°F]) and hypercapnia (end-tidal carbon dioxide concentration, 59 mm Hg) developed. Control of hyperthermia was attempted with movement of air over the dog by use of a fan and application of ethanol and ice to its skin, close to the large vessels. Hypercapnia was treated by use of manual intermittent positive pressure ventilation provided via an anesthesia circuit. Hyperthermia resolved with these treatments and did not recur. At 5.5 hours after the overdose, inhalant anesthesia was discontinued, but the dog received continuous rate IV infusions of propofol (1 mg/kg/h) and diazepam (0.25 mg/kg/h [0.11 mg/lb/h]), and the dog was ventilated by use of a mechanical ventilator.d Additionally, the dog received continuous rate IV infusions of naloxone (0.02 mg/kg/h [0.009 mg/lb/h]) and a crystalloid solution (2X maintenance fluid rate; 120 mL/kg/24 h [54.55 mL/lb/24 h]). During the first several hours of mechanical ventilation, there were continued signs of myoclonus, and treatment was attempted with intermittent IV administrations of atracurium (0.1 mg/kg) every 15 to 30 minutes, pentobarbital (1 mg/kg) as needed, and a single dose of methocarbamol (40 mg/ kg [18.2 mg/lb], IV). Transient cessation of myoclonic movements was achieved following each atracurium administration, but the clinical duration of action was only 15 to 20 minutes, and no notable clinical improvement resulted from administration of either pentobarbital or methocarbamol.
A constant rate IV infusion of atracurium (0.1 mg/ kg/h) was started. This dosage initially controlled the myoclonus effectively, but needed to be increased over the next few hours to a final rate of 0.3 mg/kg/h (0.14 mg/lb/h) to prevent movement. Ventilation parameters were monitored periodically via arterial blood gas analyses and were within reference limits at all assessments. Beginning at approximately 15 hours after the overdose, the dog developed mild hypertension (SAP, 186 mm Hg; reference range, 100 to 120 mm Hg) and bradycardia (51 beats/min; reference range, 75 to 90 beats/min); it was speculated that these abnormalities had developed as results of increased intracranial pressure (Cushing's reflex), and treatment with mannitol (15 g, IV; duration of administration, 15 minutes) was provided. Following mannitol administration, the heart rate increased, but the blood pressure did not change appreciably. Approximately 4 hours later, heart rate had decreased to < 40 beats/min and SAP had increased to approximately 190 mm Hg. Mannitol (30 g, IV; duration of infusion, 20 minutes) was administered again with no change in either variable, and a constant rate IV infusion of sodium nitroprusside (2 μg/kg/h [0.91 μg/lb/h]) was started in an attempt to control hypertension.
At approximately 22 hours after receiving the overdose, the dog was weaned from mechanical ventilation by slow discontinuation of the propofol, atracurium, naloxone, and diazepam constant rate infusions. As the dog recovered, spontaneous ventilation was resumed and the ventilatory support was discontinued. The dog was able to breath spontaneously with no ventilatory abnormalities detectable via arterial blood gas analyses. Following extubation, myoclonus was no longer present, although the dog was stuporous.
Approximately 29 hours following the overdose, the dog became dysphoric, constantly vocalized, and developed hypertension (SAP, 227 mm Hg) despite continued sodium nitroprusside infusion. A constant rate IV infusion of naloxone was resumed (0.02 mg/kg/h), and midazolam (0.5 mg/kg/h [0.23 mg/lb/h]) was added with no reduction in the frequency of vocalization or decrease in SAP. A constant rate IV infusion of medetomidine (1 μg/kg/h) was initiated, which provided control of the dysphoria and decreased SAP to approximately 160 mm Hg.
The dog continued to receive this treatment combination until 42 hours after the overdose; at that time, the dosage of naloxone was decreased to 0.01 mg/kg/ h (0.0045 mg/lb/h) and then discontinued, and the dosage of midazolam was decreased to 0.25 mg/kg/h. Within 1 hour, the dog became dysphoric and hypertensive again, and all of the constant rate infusions were resumed (naloxone, 0.02 mg/kg/h; midazolam, 0.5 mg/ kg/h; and medetomidine, 1 μg/kg/h).
At 49 hours after the overdose, the sodium nitroprusside infusion was discontinued, and the SAP was maintained at approximately 170 mm Hg. At 60 hours after the overdose, the dog's mentation improved, including recognition of caregivers and response to voice commands. Over the following 6 hours, the remaining infusions were slowly tapered and discontinued, at the conclusion of which the dog was no longer dysphoric, responded appropriately to stimuli, ate and drank readily, and was able to walk outside. No neurologic abnormalities were detectable at the time of discharge from the VTH (approx 68 hours after the overdose), and no abnormalities were evident at a recheck evaluation 1 week later.
Veterinary Teaching Hospital
Systolic arterial blood pressure
Dinamap Plus, Critikon, Tampa, Fla.
Morphine sulfate PF (1 mg/mL), Hospira, Lake Forest, Ill.
Morphine sulfate PF (25 mg/mL), Hospira, Lake Forest, Ill.
Servo 300, Siemens-Elema AB, Solna, Sweden.
Hagen N, Swanson R. Strychnine-like multifocal myoclonus and seizures in extremely high-dose opioid administration: treatment strategies. J Pain Symptom Manage 1997;14:51–58.
Kona-Boun JJ, Pibarot P, Quesnel A. Myoclonus and urinary retention following subarachnoid morphine injection in a dog. Vet Anaesth Analg 2003;30:257–264.
Cannesson M, Nargues N, Bryssine B, et al. Intrathecal morphine overdose during combined spinal-epidural block for caesarean delivery. Br J Anaesth 2002;89:925–927.
Andersen G, Christrup L, Sjogren P. Relationships among morphine metabolism, pain and side effects during long-term treatment: an update. J Pain Symptom Manage 2003;25:74–91.
De Conno F, Caraceni A, Martini C, et al. Hyperalgesia and myoclonus with intrathecal infusion of high-dose morphine. Pain 1991;47:337–339.
Werz MA, MacDonald RL. Opiate alkaloids antagonize postsynaptic glycine and GABA responses: correlation with convulsant action. Brain Res 1982;236:107–119.
Okura T, Saito M, Nakanishi M, et al. Different distribution of morphine and morphine-6 B-glucuronide after intracerebroventricular injection in rats. Br J Pharmacol 2003;140:211–217.
Sandouk P, Serrie A, Scherrmann JM, et al. Presence of morphine metabolites in human cerebrospinal fluid after intracerebroventricular administration of morphine. Eur J Drug Metab Pharmacokinet 1991;Spec No 3:166–171.
Hemstapat K, Smith SA, Monteith GR, et al. The neuroexcitatory morphine metabolite, morphine-3-glucuronide (M3G), is not neurotoxic in primary cultures of either hippocampal or cerebellar granule neurones. Pharmacol Toxicol 2003;93:197–200.
Pelligrino DA, Riegler FX, Albrecht RF. Ventilatory effects of fourth cerebroventricular infusions of morphine-6- or morphine-3-glucuronide in the awake dog. Anesthesiology 1989;71:936–940.
Sjogren P, Thunedborg LP, Christrup L, et al. Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration? Six case histories. Acta Anaesthesiol Scand 1998;42:1070–1075.
Stoelting R. Opioid agonists and antagonists. In:Stoelting R, ed.Pharmacology and physiology in anesthetic practice. 3rd ed.Baltimore: Lippincott Williams & Wilkins, 1999;1999
Groudine SB, Cresanti-Daknis C, Lumb PD. Successful treatment of a massive intrathecal morphine overdose. Anesthesiology 1995;82:292–295.