Quantitative sensory testing in canine musculoskeletal pain: Findings from a systematic review, meta-analysis feasibility assessment, and limitations.

Quantitative sensory testing (QST) allows the study of pain mechanisms, patient phenotyping, and response to therapy. The goals of this study were to conduct a systematic review of the use of QST in dogs with musculoskeletal disease including osteoarthritis (OA), and to assess, by means of a meta-analysis, the ability of QST to differentiate affected dogs from healthy controls. The study protocol was registered; three bibliographic databases were screened. Studies involving QST in healthy dogs and those with musculoskeletal disease were included. Data were extracted using a standardized form. Assessment of quality and risk of bias were performed using the CAMARADES critical assessment tool. Twenty-nine articles met the inclusion criteria [systematic review (n = 11); meta-analysis (n = 28)]. In the systematic review, ten studies performed static QST: mechanical [punctate tactile (n = 6); mechanical pressure (n = 5)]; thermal [cold (n = 3); hot (n = 4)]; electrical (n = 1); and one study performed dynamic QST [conditioned pain modulation (n = 1)]. Most studies were of good scientific quality and showed low to moderate risk of bias. A meta-analysis was not possible due to numerous and severe issues of heterogeneity of data among studies. Methods to reduce risk of bias and use of reporting guidelines are some of the most needed improvements in QST research in dogs. Standardization of QST methodology is urgently needed in future studies to allow for data synthesis and a clear understanding of the sensory phenotype of dogs with and without chronic pain including OA.

Quantitative sensory testing in feline osteoarthritic pain - a systematic review and meta-analysis.

Quantitative sensory testing (QST) is a psychophysical test used to quantify somatosensory sensation under normal or pathological conditions including osteoarthritis (OA). OBJECTIVE: This study aimed to conduct a systematic review and meta-analysis of studies using QST in healthy and osteoarthritic cats, registered at Systematic Review Research Facility (#26-06-2017). DESIGN: Hierarchical models with random intercepts for each individual study extracted through the systematic review were fit to subject-level data; QST measures were contrasted between healthy and osteoarthritic cats. Four bibliographic databases were searched; quality and risk of bias assessment were performed using pre-established criteria. RESULTS: Six articles were included; most were of high quality and low risk of bias. Punctate tactile threshold (n = 70) and mechanical temporal summation (n = 35) were eligible for analysis. Cats with OA have lower punctate tactile threshold [mean difference (95%HDI): -44 (-60; -26) grams] and facilitated temporal summation of pain [hazard ratio (95%HDI): 5.32 (2.19; 14) times] when compared with healthy cats. The effect of sex and body weight on sensory sensitivity remained inconclusive throughout all analyses. Due to the correlation between age and OA status, it remains difficult to assess the effect of OA on sensory sensitivity, independently of age. CONCLUSIONS: Clear and transparent reporting using guidelines are warranted. Similar to people, centralized sensitization is a feature of OA in cats. Future studies should try to elucidate the age effect on feline OA. Research with natural OA in cats is promising with potential to benefit feline health and welfare, and improve translatability to clinical research.

Rat cardiovascular telemetry: Marginal distribution applied to positive control drugs.

Cardiovascular effects are considered frequent during drug safety testing. This investigation aimed to characterize the pharmacological response of the conscious telemetered rat in vivo model to known cardiovascular active agents. These effects were analyzed using statistical analysis and cloud representation with marginal distribution curves for the contractility index and heart rate as to assess the effect relationship between cardiac variables. Arterial blood pressure, left ventricular pressure, electrocardiogram and body temperature were monitored. The application of data cloud with marginal distribution curves to heart rate and contractility index provided an interesting tactic during the interpretation of drug-induced changes particularly during selective time resolution (i.e. marginal distribution curves restricted to Tmax). Taken together, the present data suggests that marginal distribution curves can be a valuable interpretation strategy when using the rat cardiovascular telemetry model to detect drug-induced cardiovascular effects. Marginal distribution curves could also be considered during the interpretation of other inter-dependent parameters in safety pharmacology studies.

Assessing experimental visceral pain in dairy cattle: A pilot, prospective, blinded, randomized, and controlled study focusing on spinal pain proteomics.

Few studies have verified the validity of behavioral and physiological methods of pain assessment in cattle. This prospective, blinded, randomized controlled experimental study aimed to validate different methods of pain assessment during acute and chronic (up to 21 d postintervention) conditions in dairy cattle, in response to 3 analgesic treatments for traumatic reticuloperitonitis. Cerebrospinal fluid (CSF) biomarkers and mechanical sensitization were measured as indicators of centralized pain. Proteomics in the CSF were examined to detect specific (to pain intensity) and sensitive (responsive to analgesia) markers. Recordings of spontaneous behavior with video analysis, telemetered motor activity, pain scales, electrodermal activity, and plasma cortisol concentration were quantified at regular intervals. Cows were assigned to group 1 (n=4, standard control receiving aspirin), group 2 (n=5, test group receiving preemptive tolfenamic acid), or group 3 (n=3, positive control receiving preemptive multimodal analgesia composed of epidural morphine, plus tolfenamic acid and butorphanol). Rescue analgesia was administered as needed. Generalized estimating equations tested group differences and the influence of rescue analgesia on the measurements. All 3 groups demonstrated a long-term decrease in a CSF protein identified as transthyretin. The decrease in transthyretin expression inversely correlated with the expected level of analgesia (group 1<2<3). Moreover, in group 1, CSF noradrenaline decreased long term, cows were hypersensitive to mechanical stimulation, and they demonstrated signs of discomfort with higher motor activity and "agitation while lying" recorded from video analysis. Decreased "feeding behavior," observer-reported pain scales, electrodermal activity, and plasma cortisol concentration were inconsistent to differentiate pain intensity between groups. In summary, changes in CSF biomarkers and mechanical sensitization reflected modulation of central pain in dairy cows. The spontaneous behavior "agitation while lying" was the only behavioral outcome validated for assessing acute and chronic pain in this visceral pain model.

Characterization of osteoarthritis in cats and meloxicam efficacy using objective chronic pain evaluation tools.

This study aimed to characterize osteoarthritis (OA)-related chronic pain and disability in experimental cats with naturally occurring OA. Peak vertical ground reaction force (PVF), accelerometer-based motor activity (MA) and the von Frey anesthesiometer-induced paw withdrawal threshold were used to define OA and to test the efficacy of meloxicam. A diagnosis of OA was based on radiographic and orthopedic examinations. Cats with OA (n=39) and classified as non-OA (n=6) were used to assess the reliability and sensitivity of the parameters to assess OA over 3weeks while being administered placebo medication. A randomised parallel design study was then used to investigate the effects on OA of daily oral meloxicam treatment for 4weeks at different dose rates (0.025mg/kg, n=10mg/kg; 0.04mg/kg, n=10; 0.05mg/kg, n=9), compared to cats administered a placebo (n=10). The test-retest repeatability for each tool was good (intra-class correlation coefficient ⩾0.6). The PVF and the von Frey anesthesiometer-induced paw withdrawal threshold discriminated OA (P<0.05). Meloxicam did not add to the PVF improvement observed in placebo-treated cats during the treatment period (adj-P⩽0.01). The 0.025 and the 0.05mg/kg meloxicam-treated cats experienced a higher night-time (17:00-06:58h) MA intensity during the treatment period compared to the placebo period (adj-P=0.04, and 0.02, respectively) and this effect was not observed in the placebo group. The high allodynia rate observed in the 0.04mg/kg meloxicam-treated group may explain the lower responsiveness to the drug. The von Frey anesthesiometer-induced paw withdrawal threshold demonstrated no responsiveness to meloxicam. The results from this study indicated that daily oral meloxicam administration for 4weeks provided pain relief according to night-time MA.

Effects of feeding a high omega-3 fatty acids diet in dogs with naturally occurring osteoarthritis.

The aim of this randomized, placebo-controlled and double-blinded trial was to compare the effect of a veterinary therapeutic diet (VTD) rich in omega-3 fatty acids (omega-3) from fish origin to a regular diet used as control (CTR) over a period of 13 weeks in dogs afflicted by naturally occurring osteoarthritis (OA). Thirty privately owned dogs were selected. Dogs had lameness confirmed by an orthopaedic examination, had stifle/hip OA and had locomotor disability based on the peak of the vertically oriented ground reaction force (PVF) measured using a force platform. At Baseline, all owners were asked to determine 2-5 activities of daily living that were the most impaired. Activities were scores (0-4) in accordance with severity using case-specific outcome measures (CSOM). The PVF was also measured. Dogs (15/group) were then randomly assigned to receive either the CTR or the VTD. The CSOM was completed twice weekly. The recording of PVF was repeated at Week 7 and 13. The VTD-fed dogs showed a significantly higher PVF at Week 7 (p < 0.001) and at Week 13 (p < 0.001) when compared to Baseline. From Baseline to Week 13, VTD-fed dogs had a mean (± SD) change in PVF recording of 3.5 ± 6.8% of body weight (%BW) compared with 0.5 ± 6.1%BW (p = 0.211) in CTR-fed dogs. This change in primary outcome was consistent with an effect size of 0.5. Conversely, dogs fed the CTR did not show significant change in PVF measurements. At the end of the study, the CSOM was significantly decreased (p = 0.047) only in VTD fed dogs. In lame OA dogs, a VTD that contains high level of omega-3 from fish origin improved the locomotor disability and the performance in activities of daily living. Such nutritional approach appears interesting for the management of OA.

Pain induced by a minor medical procedure (bone marrow aspiration) in dogs: comparison of pain scales in a pilot study.

BACKGROUND: Bone marrow aspiration (BMA) is a clinical procedure frequently performed in dogs. OBJECTIVE: To compare levels of pain intensity induced by 3 different BMA procedures using several pain scoring instruments. ANIMALS: Sixteen healthy Beagles. METHODS: A prospective experimental pilot study was conducted using blinded observers. Dogs were randomized into 3 groups: iliac BMA under sedation (Iliac-Sed, n = 4), sternum BMA under sedation (Stern-Sed, n = 4), and sternum BMA on conscious dogs without sedation (Stern-No-Sed, n = 8). RESULTS: Using the SF-Glasgow pain scale, the overall pain score in the Stern-No-Sed group was lower than that in the Stern-Sed group (P = 0.04). Using the 4A-VET pain scale, the effects of procedures over time on pain scores did not differ between and within groups. An inactivity index indicated that the overall score for the Stern-No-Sed group was significantly lower than the scores for the Stern-Sed and Iliac-Sed groups (P ≤ 0.01). There was a significant association in pain assessment using the SF-Glasgow and 4A-VET pain scales (P = 0.0004). When comparing the SF-Glasgowscale to the 4A-VET pain scale, the scores for the Stern-No-Sed group were lower compared to those of the Stern-Sed scores (P = 0.03). Based on telemetered motor activity, the Iliac-Sed group may have experienced more discomfort during the post-procedural period. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs may experience mild to moderate pain after BMA procedures, and the sternal site should be preferred. The SF-Glasgow pain scale showed better interobserver reliability, but the 4A-VET scale was less biased by sedation.

Evaluation of a novel ECG lead placement method in telemetered freely moving cynomolgus monkeys: assessment of an intravascular biopotential lead.

INTRODUCTION: ECG is considered as a critical biomarker of cardiac safety pharmacology. ECG signal quality is essential for accurate interval quantification and automated arrhythmia detection. METHODS: We evaluated ECG signal quality over a 6 month period from 15 cynomolgus monkeys with radiotelemetry transmitters using biopotential leads where the negative lead was inserted in the jugular vein and advanced to the superior vena cava (intravascular lead) and the positive lead was placed on the diaphragm at the apex of the heart (diaphragmatic lead). Signal noise and signal-to-noise ratio from this implantation methodology were compared with signals obtained from animals with subcutaneous ECG lead. Macroscopic pathology and histopathology associated with the intravascular lead were evaluated at 6 months post-implantation in six monkeys. RESULTS: The ECG morphology obtained with the intravascular/diaphragmatic lead placement was comparable to conventional subcutaneous ECG (emulating Lead II) but presented higher amplitudes (P-wave +50.0%; R-wave +30.0%). Signal noise showed a circadian cycle of changes in magnitude for subcutaneous ECG leads that was not observed with this method. The intravascular/diaphragmatic lead placement presented a higher signal-to-noise ratio than subcutaneous ECG leads. No macroscopic abnormality was observed to be associated with the intravascular lead. Mild thickening of the intima/subintima with mild intimal proliferation of the cranial vena cava surrounding the intravascular lead were noted at histopathological examination. DISCUSSION: The intravascular/diaphragmatic ECG lead placement in cynomolgus monkeys provided reduced signal noise and elevated P-QRS-T amplitudes. The intravascular lead was well tolerated and appeared suitable for chronically instrumented cardiovascular safety pharmacology studies. Further assessments would be warranted to evaluate the potential of this methodology in other species.

Cardiovascular and respiratory safety pharmacology in Göttingen minipigs: Pharmacological characterization.

INTRODUCTION: Similarities between pigs and humans support the relevance of Göttingen minipigs for regulatory safety pharmacology. The minipig is the species of choice for cardiovascular safety pharmacology when pivotal repeat toxicology studies are conducted in this species. METHODS: 4 male Göttingen minipigs with cardiovascular telemetry transmitters received intravenous saline, esmolol (0.5, 1, 2, 4 and 8mg/kg), medetomidine (0.04mg/kg), remifentanil (0.5, 1, 2, 4, 8 and 16µg/kg) and dopamine (2, 8, 10, 20, 30 and 50µg/kg/min) and oral sotalol (3 and 10mg/kg). Respiratory monitoring was conducted in 3 male and 3 female Göttingen minipigs receiving intravenous saline and methacholine (0, 3.4, 13.5 and 68µg/kg). RESULTS: Heart rate (HR) corrected QT was optimal with a method based on analysis of covariance (QTca) followed by Fridericia's standard formula. Esmolol induced a decrease in HR. Medetomidine was associated with an initial hypertension with bradycardia followed by sustained hypotension, bradycadia and prolonged QTc. Remifentanil induced a dose-dependent QTc shortening with an increase in arterial pressures. Sotalol caused a decrease in HR and systolic arterial pressure with an increase in PR and QTc intervals. Dopamine induced an increase in arterial and pulse pressures. Methacholine increased tidal volume, respiratory rate and minute volume. DISCUSSION: The results suggest that the minipig is a valid alternative to other non-rodent species for cardiovascular and respiratory safety pharmacology studies when this species is justified.

Patlak plot analysis CT-GFR for the determination of renal function: comparison of normal dogs with autologous kidney transplant dogs.

Glomerular filtration rate (GFR) can be determined using Patlak plot analysis with single-slice dynamic computed tomography (CT). Acute autologous graft failure has several causes, all of which induce a measurable decrease in glomerular filtration rate. This study demonstrated in an experimental model of canine autologous renal transplant that CT-derived renal plasma clearance was significantly lower (p = 0.002) in dogs having undergone transplant (0.077 +/- 0.058 ml min(-1) ml renal tissue(-1)) compared with control dogs (0.396 +/- 0.139 ml min(-1) ml renal tissue(-1)). A significant negative curvilinear relationship was seen between serum creatinine and total renal plasma clearance (R(2) = 0.84, p = 0.0001). Alterations in renal time attenuation curve shape in dogs having undergone transplant may have been related to increased renal vascular resistance related to tubular necrosis. CT-GFR may be a useful experimental tool in the evaluation of renal dysfunction in transplant models.

Combined cardiopulmonary assessments with implantable telemetry device in conscious freely moving cynomolgus monkeys.

Female cynomolgus monkeys were surgically implanted with telemetry transmitters recording ECG (DII), arterial pressure, physical activity, body temperature, and tidal volume. Respiratory rate (RR) and tidal volume (TV) were monitored simultaneously with the telemetry transmitter using impedance. Impedance-based monitoring of RR and TV by telemetry correlated with controlled TV and with pneumotachometer (>98%) in restrained animals. Control drugs with cardiovascular and respiratory effects, including saline, medetomidine (0.01, 0.02 and 0.04mg/kg) and cocaine (0.5, 1.0 and 1.5mg/kg) were administered intravenously. An averaging epoch of 5min was used for analysis of respiratory data. Medetomidine induced significant respiratory depression with decrease in RR and TV in freely moving animals while cocaine increased TV, RR and minute ventilation (MV) with concomitant increase in heart rate when compared with time matched values from saline-treated animals. The onset, duration and magnitude of cardiovascular and respiratory changes were correlated. This highlights the dependency of the cardiovascular and respiratory systems. The use of cardiopulmonary monitoring can allow continuous monitoring including during night time when variability of respiratory parameters is lower. Monitoring of cardiovascular and respiratory parameters in the same animals could also help to decrease the number of animals used in research.

Video-electroencephalography in conscious non human primate using radiotelemetry and computerized analysis: refinement of a safety pharmacology model.

INTRODUCTION: Electroencephalography (EEG) investigations are occasionally required as follow-up studies for safety pharmacology core battery (S7A). Video-EEG monitoring is a standard diagnostic tool in humans but limited data is available on its use in telemetered freely moving macaque monkeys for safety pharmacology investigations. While proconvulsant risk evaluations are routinely conducted in rodents, pharmacological or pharmacokinetic considerations lead to the use of non human primates in toxicology and safety pharmacology in some cases. METHODS: Cynomolgus monkeys were instrumented with telemetry implants. Placement of EEG electrode was based on the 10-20 system using three derivations (C3-O1, Cz-Oz and C4-O2). EEG trace analysis was carried out using NeuroScore software. After 24 h of continuous video-EEG monitoring, animals received pentylenetetrazole (PTZ, 10 mg/kg/15 min) until convulsions were noted. Convulsions were immediately treated with diazepam (1.0 mg/kg). A seizure detection protocol with a dynamic spike train threshold was used for the entire EEG monitoring period (total of 44 h) including periods when PTZ was administered. Spectral analysis was done to quantify the absolute and relative amplitude of EEG frequency bands (delta, theta, alpha, sigma and beta waves). Sleep stages were quantified and EEGs during seizures were analyzed using fast Fourier transformation (FFT) to assess dominant frequencies. RESULTS: Spike trains were detected by computerized analysis in all animals presenting PTZ-induced seizures while paroxysmal activities were systematically predictive (at least 4-min prior to generalized seizures). Beta activity increased with visual stimulation using monkey treats. Characteristics of EEG for all sleep stages (I, II, III and IV) were present in all animals. Delta activity was predominant in normal awake EEG as well as in all sleep stages. Seizure peak frequency was 3-6 Hz on FFT, corresponding to the discharge of the underlying generator. DISCUSSION: EEG-video monitoring can be useful when using non human primates to characterize neurological adverse effects with unpredictable onset. Computerized video-EEG analysis was a valuable tool for safety pharmacology investigations including proconvulsant risk assessment, spectral analysis of frequency bands and sleep stage determination.

Conscious and anesthetized non-human primate safety pharmacology models: hemodynamic sensitivity comparison.

INTRODUCTION: Drug-induced cardiovascular effects identified in conscious cynomolgus monkeys equipped with tethers and prepared for radiotelemetry were compared with results from anesthetized non-human primate (cynomolgus and rhesus) models. METHODS: Remifentanil (4.0 microg/kg, bolus), esmolol (2.0 mg/kg, bolus) and dopamine (0.05 mg/kg/min, 30 min infusion) were given intravenously to all models. RESULTS: Remifentanil decreased heart rate (HR), systolic, mean and diastolic systemic arterial pressures (SAP) in anesthetized animals while conscious monkeys presented an increase in HR, systolic, mean and diastolic SAP, as seen in humans for the respective state of consciousness (conscious and anesthetized). Esmolol decreased HR, systolic, mean and diastolic SAP in anesthetized monkeys while only HR, systolic and mean SAP achieved a statistically significant decrease in the conscious model. The amplitude of SAP reduction was greater in anesthetized models, while the amplitude of HR reduction was greater in the conscious and anesthetized cynomolgus models than in the anesthetized rhesus model. Dopamine induced a significant increase in HR, systolic, mean and diastolic SAP in anesthetized models without any statistically significant effect on HR and SAP in the conscious model. DISCUSSION: The amplitude of hemodynamic and chronotropic alterations induced by positive control drugs was generally greater in anesthetized than in conscious models and statistical significance was achieved more often with the anesthetized models. These results suggest that an anesthetized model may be valuable as part of a drug screening program for cardiovascular safety evaluations in addition to a conscious model.

Temporal assessment of bone marrow lesions on magnetic resonance imaging in a canine model of knee osteoarthritis: impact of sequence selection.

OBJECTIVE: To assess the evolution of bone marrow lesions (BMLs) in a canine model of knee osteoarthritis (OA) using three different magnetic resonance imaging (MRI) sequences. DESIGN: Three MRI sequences [coronal, T1-weighted three-dimensional fast gradient recalled echo (T1-GRE), sagittal fat-suppressed 3D spoiled gradient echo at a steady state (SPGR), and sagittal T2-weighted fast spin echo with fat saturation (T2-FS)] were performed at baseline, and at week 4, 8 and 26 in five dogs following transection of the anterior cruciate ligament. The same reader scored (0-3) subchondral BMLs twice, in blinded conditions, according to their extent in nine joint subregions, for all imaging sessions, and independently on the three MRI sequences. Correlation coefficients and Bland-Altman plots evaluated intra-reader repeatability. Readings scores were averaged and the nine subregions were summed to generate global BML scores. RESULTS: BMLs were most prevalent in the central and medial portions of the tibial plateau. Intra-reader repeatability was good to excellent for each sequence (r(s)=0.87-0.97; P<0.001). Maximal intra-reader variability (24%) was reached on T2-FS and was associated to higher scores (P<0.05). Global BML scores increased similarly on all three sequences until week 8 (P<0.05). At week 26, score on T2-FS was decreased, being lower when compared to T1-GRE and SPGR (P<0.05). CONCLUSION: In this canine OA model, the extent of BMLs varies in time on different MRI sequences. Until the complex nature of these lesions is fully resolved, it is suggested that to accurately assess the size and extent of BMLs, a combination of different sequences should be used.

Magnetic resonance imaging can accurately assess the long-term progression of knee structural changes in experimental dog osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) structural changes take place over decades in humans. MRI can provide precise and reliable information on the joint structure and changes over time. In this study, we investigated the reliability of quantitative MRI in assessing knee OA structural changes in the experimental anterior cruciate ligament (ACL) dog model of OA. METHODS: OA was surgically induced by transection of the ACL of the right knee in five dogs. High resolution three dimensional MRI using a 1.5 T magnet was performed at baseline, 4, 8 and 26 weeks post surgery. Cartilage volume/thickness, cartilage defects, trochlear osteophyte formation and subchondral bone lesion (hypersignal) were assessed on MRI images. Animals were killed 26 weeks post surgery and macroscopic evaluation was performed. RESULTS: There was a progressive and significant increase over time in the loss of knee cartilage volume, the cartilage defect and subchondral bone hypersignal. The trochlear osteophyte size also progressed over time. The greatest cartilage loss at 26 weeks was found on the tibial plateaus and in the medial compartment. There was a highly significant correlation between total knee cartilage volume loss or defect and subchondral bone hypersignal, and also a good correlation between the macroscopic and the MRI findings. CONCLUSION: This study demonstrated that MRI is a useful technology to provide a non-invasive and reliable assessment of the joint structural changes during the development of OA in the ACL dog model. The combination of this OA model with MRI evaluation provides a promising tool for the evaluation of new disease-modifying osteoarthritis drugs (DMOADs).

Development of a composite orthopaedic pain scale in horses.

This study addresses development and validation of a composite multifactorial pain scale (CPS) in an experimental equine model of acute orthopaedic pain. Eighteen horses were allocated to control (sedation with/without epidural analgesia - mixture of morphine, ropivacaine, detomidine and ketamine) and experimental groups: amphotericin-B injection in the tarsocrural joint induced pain and analgesia was either i.v. phenylbutazone administered post-induction of synovitis, or pre-emptive epidural mixture, or a pre-emptive combination of the 2. Inter- and intra-observer reproducibility was good (0.8

Brown bear (Ursus arctos arctos) femoral head and neck excision.

A 30-yr-old untamed European female brown bear (Ursus arctos arctos) with a craniodorsal luxation of the right femoral head and bilateral degenerative joint disease of the coxofemoral joint had a femoral head and neck excision following unsatisfactory conservative medical therapy. The bear was injected with zolazepam-tiletamine, and anesthesia was induced with i.v. thiopental and maintained with isoflurane in oxygen via endotracheal tube. A lumbosacral epidural injection of medetomidine-bupivacaine provided additional analgesia. Slight initial cardiorespiratory depression was counteracted with fluid and inotropic drug administration and ventilatory assistance. The bear's gluteal muscle anatomy differs from that of the dog. Recovery was uneventful. The bear was confined indoors for 6 wk and was able to ambulate normally within 6 mo.