Lesley J. Smith

Continual systemic infusion of lidocaine provides analgesia in an animal model of neuropathic pain.

&NA; We examined whether continual constant‐rate infusion of lidocaine would provide analgesia during the initial post‐injury phase in the chronic constriction injury model of neuropathic pain. Male Sprague–Dawley rats were divided into control and ligated groups and infused with saline or lidocaine (0.15, 0.33, 0.67, and 1.3 mg/kg/h) via subcutaneously implanted Alzet® osmotic minipumps. Thermal withdrawal latencies were obtained prior (Day 0) and 3 days after loose sciatic ligation and pump implantation surgery. Ligated animals receiving lidocaine at 0.67 or 1.3 mg/kg/h exhibited no change in withdrawal latency on Day 3 after surgery, indicating that lidocaine at these doses prevented the development of thermal hyperalgesia as a sign of neuropathic pain. In contrast, ligated animals treated with saline or lidocaine at 0.15 or 0.33 mg/kg/h exhibited hyperalgesia on Day 3 after surgery, indicating that these lower doses of lidocaine failed to provide analgesia. Control animals treated with saline or any of the lidocaine doses exhibited no change in withdrawal latencies between Day 0 and Day 3. In a separate group of ligated animals, lidocaine infusion (0.67 mg/kg/h) that was started 24 h after sciatic ligation surgery reversed the already present thermal hyperalgesia. Average plasma lidocaine concentrations were 0.11, 0.36, and 0.45 &mgr;g/ml for animals receiving 0.33, 0.67 and 1.3 mg/kg/h of lidocaine, respectively. These results suggest that continual systemic infusion of lidocaine prevents or reverses the development of neuropathic pain following chronic constriction injury. These results add to the increasing body of evidence supporting the therapeutic value of preemptive and post‐operative lidocaine administration for the relief of neuropathic pain.

Effectiveness of injection of local anesthetic into the retrobulbar space for postoperative analgesia following eye enucleation in dogs

OBJECTIVE To assess the efficacy of a retrobulbar bupivacaine nerve block for postoperative analgesia following eye enucleation in dogs. DESIGN Randomized controlled trial. ANIMALS 22 dogs. PROCEDURES Client-owned dogs admitted to the hospital for routine eye enucleation were enrolled with owner consent and randomly assigned to a treatment (bupivacaine hydrochloride) or control (saline [0.9% NaCl] solution) group. Baseline subjective pain scores were recorded. Anesthesia consisted of hydromorphone and midazolam preoperatively, thiopental or propofol for induction, and isoflurane in oxygen for maintenance. An inferior-temporal palpebral retrobulbar injection of either saline solution or bupivacaine was administered. Transpalpebral eye enucleation was performed. Pain scores were recorded at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after extubation (time 0) by observers masked to treatment groups. Dogs were given hydromorphone (0.2 mg/kg [0.09 mg/lb], IM or IV) as a rescue analgesic if the subjective pain score totaled >or= 9 (out of a maximum total score of 18) or >or= 3 in any 1 category. RESULTS 9 of 11 control dogs required a rescue dose of hydromorphone, but only 2 of 11 dogs in the bupivacaine treatment group required rescue analgesia. Mean time to treatment failure (ie, administration of rescue analgesia following extubation) was 0.56 hours (95% confidence interval, 0.029 to 1.095 hours) for the 11 dogs that received hydromorphone. CONCLUSIONS AND CLINICAL RELEVANCE Retrobulbar administration of bupivacaine in dogs in conjunction with traditional premedication prior to eye enucleation was an effective form of adjunctive analgesia and reduced the need for additional postoperative analgesics.

A comparison of epidural buprenorphine with epidural morphine for postoperative analgesia following stifle surgery in dogs

Objective To compare the efficacy of epidural buprenorphine with epidural morphine for post-operative pain relief in dogs undergoing cranial cruciate ligament rupture repair. Study design A randomized, double blind clinical trial. Animals Twenty client-owned dogs with cranial cruciate ligament rupture. Methods Dogs were randomly assigned to receive either epidural buprenorphine (4 µg kg-1) or epidural morphine (0.1 mg kg-1) in a total volume of 0.2 mL kg-1. Epidural injections were performed immediately after induction of anesthesia. End-tidal halothane and CO2 were recorded every 15 minutes from the time of epidural administration of drug to extubation. A numerical rating pain score system was used by a blinded observer to evaluate analgesia beginning at extubation and continuing at specific intervals for 24 hours after surgery. Heart rate, respiratory rate, and blood pressure were recorded noninvasively at the same times. If pain score indicated moderate discomfort, rescue morphine at 1.0 mg kg-1 was administered intramuscularly. Results There were no significant differences between groups with respect to pain score, heart rate, respiratory rate, indirect blood pressure, end-tidal halothane or end-tidal CO2 at any time point. Fifty percent of dogs in the buprenorphine group and 50% of dogs in the morphine group required rescue analgesic medication. Time of systemic rescue morphine administration did not differ significantly between the two groups. There were no clinically observable side-effects from epidural administration of either drug in any of the dogs of this study. Conclusions Epidural buprenorphine is as effective as epidural morphine for the relief of postoperative hindlimb orthopedic pain in dogs. Clinical relevance Buprenorphine appears to be an effective opioid for epidural use in healthy dogs. Buprenorphine may offer certain advantages over morphine for epidural use, such as lower abuse potential and, in some clinics, reduced cost and less wastage of drug.

Pharmacokinetics of hydromorphone hydrochloride in healthy dogs

OBJECTIVE To assess the pharmacokinetics of hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs. STUDY DESIGN Randomized experimental trial. ANIMALS Seven healthy male neutered Beagles aged 12.13 +/- 1.2 months and weighing 11.72 +/- 1.10 kg. METHODS The study was a randomized Latin square block design. Dogs were randomly assigned to receive hydromorphone hydrochloride 0.1 mg kg(-1) or 0.5 mg kg(-1) IV (n = 4 dogs) or 0.1 mg kg(-1) (n = 6) or 0.5 mg kg(-1) (n = 5) SC on separate occasions with a minimum 14-day washout between experiments. Blood was sampled via a vascular access port at serial intervals after drug administration. Serum was analyzed by mass spectrometry. Pharmacokinetic parameters were determined with computer software. RESULTS Serum concentrations of hydromorphone decreased quickly after both routes of administration of either dose. The serum half-life, clearance, and volume of distribution after IV hydromorphone at 0.1 mg kg(-1) were 0.57 hours (geometric mean), 106.28 mL minute(-1) kg(-1), and 5.35 L kg(-1), and at 0.5 mg kg(-1) were 1.00 hour, 60.30 mL minute(-1) kg(-1), and 5.23 L kg(-1), respectively. The serum half-life after SC hydromorphone at 0.1 mg kg(-1) and 0.5 mg kg(-1) was 0.66 hours and 1.11 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Hydromorphone has a short half-life, suggesting that frequent dosing intervals are needed. Based on pharmacokinetic parameters calculated in this study, 0.1 mg kg(-1) IV or SC q 2 hours or a constant rate infusion of hydromorphone at 0.03 mg kg(-1) hour(-1) are suggested for future studies to assess the analgesic effect of hydromorphone.

Evaluation of topical nalbuphine or oral tramadol as analgesics for corneal pain in dogs: a pilot study

OBJECTIVE To evaluate the effectiveness of topical nalbuphine or oral tramadol in the treatment of corneal pain in dogs. ANIMALS STUDIED Fourteen male Beagle dogs. PROCEDURES Dogs were divided into three treatment groups and sedated with dexmedetomidine (5 μ/kg IV). A 4 mm corneal epithelial wound was created in the right eye (OD) of all dogs. Sedation was reversed with atipamazole IM. All dogs received pre/post ophthalmic examinations. Post operatively, Group NB (n = 5) received topical 1% preservative-free nalbuphine OD q8 h and an oral placebo PO q8 h. Group TR (n = 5) received tramadol (4 mg/kg) PO q8 h and topical sterile saline OD q8 h. Group CNTRL (n = 4) received topical sterile saline OD q8 h and an oral placebo q8 h. All dogs received topical 0.3% gentamicin OD TID until healed. Dogs were pain scored using a pain scoring system modified from the University of Melbourne pain scale at 0, 1, 2, 4, and 6 h, then every 6 h by observers masked to treatment, until corneal wounds were healed. Treatment failure was recorded if cumulative pain scores were above a minimum threshold of acceptable pain and rescue analgesia of morphine (1.0 mg/kg IM) was administered subsequently. RESULT Four dogs in Group NB, one dog in Group TR, and two dogs in Group CNTRL required rescue analgesia. There was no significant difference in the incidence of treatment failure between groups (P = 0.184). Mean time to rescue was 9.16 h. All corneal wounds were healed by 84 h. CONCLUSIONS The results of this study suggest tramadol rather than nalbuphine should be further investigated for the treatment of corneal pain.

Pharmacokinetics of a controlled‐release liposome‐encapsulated hydromorphone administered to healthy dogs

The purpose of the study was to assess the pharmacokinetics of liposome-encapsulated (DPPC-C) hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs. A total of eight healthy Beagles aged 12.13 +/- 1.2 months and weighing 11.72 +/- 1.10 kg were used. Dogs randomly received liposome encapsulated hydromorphone, 0.5 mg/kg IV (n = 6), 1.0 mg/kg (n = 6), 2.0 mg/kg (n = 6), or 3.0 mg/kg (n = 7) SC with a 14-28 day washout between trials. Blood was sampled at serial intervals after drug administration. Serum hydromorphone concentrations were measured using liquid chromatography with mass spectrometry. Serum concentrations of hydromorphone decreased rapidly after IV administration of the DPPC-C formulation (half-life = 0.52 h, volume of distribution = 12.47 L/kg, serum clearance = 128.97 mL/min/kg). The half-life of hydromorphone after SC administration of DPPC-C formulation at 1.0, 2.0, and 3.0 mg/kg was 5.22, 31.48, and 24.05 h, respectively. The maximum serum concentration normalized for dose (C(MAX)/D) ranged between 19.41-24.96 ng/mL occurring at 0.18-0.27 h. Serum hydromorphone concentrations fluctuated around 4.0 ng/mL from 6-72 h after 2.0 mg/kg and mean concentrations remained above 4 ng/mL for 96 h after 3.0 mg/kg DPPC-C hydromorphone. Liposome-encapsulated hydromorphone (DPPC-C) administered SC to healthy dogs provided a sustained duration of serum hydromorphone concentrations.

Midazolam administration reverses thermal hyperalgesia and prevents gamma-aminobutyric acid transporter loss in a rodent model of neuropathic pain.

BACKGROUND: Loss of &ggr;-aminobutyric acid (GABA) inhibition in the spinal dorsal horn may contribute to neuropathic pain. Here we examined whether systemic administration of the benzodiazepine midazolam would alleviate thermal hyperalgesia due to chronic constriction injury (CCI) of the sciatic nerve. METHODS: Hyperalgesia was evaluated with the thermal paw withdrawal latency test before, and 3 and 7 days after CCI. Animals randomly received, via osmotic minipump infusion, midazolam (2.0 mg · kg−1 · h−1), flumazenil (0.004 mg · kg−1 · h−1), midazolam plus flumazenil at the same doses, or saline (0.01 mg · kg−1 · h−1). Four groups of sham-operated rats (surgery without nerve ligation) received matched treatments. Levels of the GABA transporter 1 (GAT-1) in the lumbar spinal dorsal horn were estimated using western immunoblots 7 days after surgery. RESULTS: Saline-treated CCI rats developed thermal hyperalgesia on Day 3 with a more pronounced effect on Day 7. Continuous midazolam infusion prevented thermal hyperalgesia on both days. The antihyperalgesic effect of midazolam was reversed by the coadministration of flumazenil. Infusion of flumazenil alone had no effect on the thermal hyperalgesia in CCI rats. Sham-operated rats treated with saline, midazolam, or midazolam plus flumazenil exhibited no thermal hyperalgesia. Unexpectedly, thermal paw withdrawal latency in sham animals treated with flumazenil alone was significantly decreased. Changes in GAT-1 levels paralleled the behavior. Midazolam prevented the CCI-associated decreases, and flumazenil reversed midazolams effect. Flumazenil alone did not modify GAT-1 levels in CCI animals but in sham animals the transporter levels were significantly reduced. CONCLUSIONS: GABA inhibition plays an important role in neuropathic pain. Continuous systemic benzodiazepine administration may prove effective in alleviating neuropathic pain.

Comparison of carprofen and tramadol for postoperative analgesia in dogs undergoing enucleation.

OBJECTIVE To compare analgesia provided by carprofen and tramadol in dogs after enucleation. DESIGN Randomized, masked clinical trial. ANIMALS 43 dogs. PROCEDURES Client-owned dogs admitted for routine enucleation were randomly assigned to receive either carprofen or tramadol orally 2 hours prior to surgery and 12 hours after the first dose. Dogs were scored for signs of pain at baseline (ie, before carprofen or tramadol administration) and at 0.25, 0.5, 1, 2, 4, 6, 8, 24, and 30 hours after extubation. Dogs received identical premedication and inhalation anesthesia regimens, including premedication with hydromorphone. If the total pain score was ≥ 9 (maximum possible score of 20), there was a score ≥ 3 in any of 5 behavioral categories (highest score possible per category was 3 or 4), or the visual analog scale (VAS) score was ≥ 35 (maximum possible score of 100) combined with a palpation score > 0, rescue analgesia (hydromorphone) was administered and treatment failure was recorded. RESULTS No differences were found in age, sex, or baseline pain scores between groups. Significantly more dogs receiving tramadol required rescue analgesia (6/21), compared with dogs receiving carprofen (1/22). Pain and VAS scores decreased linearly over time. No significant differences were found in pain or VAS scores between groups at any time point (dogs were excluded from analysis after rescue). CONCLUSIONS AND CLINICAL RELEVANCE Results of this study suggested that carprofen, with opioid premedication, may provide more effective postoperative analgesia than tramadol in dogs undergoing enucleation.

Experimental pharmacodynamics and analgesic efficacy of liposome-encapsulated hydromorphone in dogs.

The purpose of this study was to determine the experimental side effects of liposome-encapsulated hydromorphone (LE-Hydro) in beagles and to evaluate LE-Hydro analgesia in dogs undergoing ovariohysterectomies (OVH). Beagles were injected subcutaneously with 1-3 mg/kg LE-Hydro or 0.1 mg/kg hydromorphone. Dogs were evaluated for sedation, temperature, respiratory rate, and heart rate. OVH dogs were injected with 2 mg/kg LE-Hydro subcutaneously or 0.2 mg/kg morphine and 0.05 mg/kg acepromazine intramuscularly. Side effects of LE-Hydro were within clinically acceptable limits. The analgesic efficacy was superior in dogs administered LE-Hydro at 12 hr postsurgically. LE-Hydro provided adequate, durable analgesia in dogs undergoing OVH.

Pharmacokinetics and behavioral effects of an extended-release, liposome-encapsulated preparation of oxymorphone in rhesus macaques.

The objectives of the study were to determine the pharmacokinetics of oxymorphone (oxy) and of ammonium sulfate-loaded, liposome-encapsulated oxymorphone (LE-ASG oxy) and to evaluate the behavioral effects of both opioid preparations by using ethographic evaluation specific to rhesus monkeys. Rhesus monkeys (n = 8) were injected with 2.0 mg/kg LE-ASG oxy s.c.. Blood samples were collected at serial time points up to 144 h in six monkeys and up to 456 h in two monkeys. Separate groups of monkeys were injected with 0.1 mg/kg oxy s.c. (n = 4) or i.v. (n = 5). Blood samples were collected at serial time points up to 24 h after injection. Pharmacokinetic parameters were calculated by using commercially available software. Behavior was recorded in a different group of 10 monkeys administered LE-ASG oxy (2.0 mg/kg s.c.) or oxy (0.1 mg/kg s.c.) on separate occasions. Behavioral evaluations were made at serial time points while monkeys were in an extended cage with a compatible stimulus animal. Oxymorphone was rapidly eliminated from the serum in the oxy group. Measurable drug was present in serum for up to 4 h after oxy was administered subcutaneously or intravenously. LE-ASG oxy was present in serum in measurable concentrations for more than 2 weeks. Neither oxy nor LE-ASG oxy produced observable sedation. LE-ASG oxy decreased some environmentally directed behaviors, but this drug formulation increased watchfulness, decreased self-directed and elimination behaviors, increased nonspecific social contact, and decreased threat behaviors. LE-ASG oxy persisted for an extended period in rhesus monkey serum and produced behavioral changes consistent with this opioid.