Subcutaneous methadone is not different than transdermal fentanyl for postoperative analgesia in dogs with thoracolumbar disc disease, using three different pain scales and von Frey Filaments, a prospective, randomised, blinded clinical study

Subcutaneous methadone is not different than transdermal fentanyl for postoperative analgesia in dogs with thoracolumbar disc disease, using three different pain scales and von Frey Filaments, a prospective, randomised, blinded clinical study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Subcutaneous methadone is not different than transdermal fentanyl for postoperative analgesia in dogs with thoracolumbar disc disease, using three different pain scales and von Frey Filaments, a prospective, randomised, blinded clinical study Alexandra F Schütter, Anika Verhoeven, Julia Tünsmeier, Sabine BR Kästner This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6201354/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Oct, 2025 Read the published version in BMC Veterinary Research → Version 1 posted 11 You are reading this latest preprint version Abstract Background Thoracolumbar disc disease is a common neurological disease in dogs, which incorporated different pain components. Multimodal analgesic treatments especially postoperatively, are often based on opiods and require an intravenous catheter for drug application. This might impede early mobilisation and physiotherapy. Different composite pain scales and sensory testing devices exist to evaluate postoperative pain behaviour in dogs. At present, no data are available to clearly recommend one tool or technique after spinal surgery over others. Therefore, the primary aim of this study was to evaluate if, subcutaneously applied methadone or transdermal fentanyl can offer sufficient postoperative analgesia in dogs after thoracolumbar neurosurgery without the necessity of keeping an intravenous access. A secondary aim was to evaluate which type of pain recognition tool would be suitable in this dogs in a clinical setting. Methods In a prospective, randomised, clinical study client fifty client owned dogs were repeatable evaluated for 96h post spinal surgery. Treatments groups M received 0.4 mg/kg methadone subcutaneously two hours before start of surgery and following this every 6 hours. Treatment group F received topical applied 2.6 mg/ kg transdermal – fentanyl, two hours before start of the surgery. Dogs were assessed using the Glasgow composite measure pain scale – short form (CMPS-SF), the Colorado State University canine acute pain scale (CPS), a visual analogue scale and von Frey Monofilaments. Treatments groups were compared using the Wilcoxen rang sum test. Correlation between the three pain score was evaluated using the Spearman Rang correlation coefficient. Results At no time point, any of the used methods could demonstrate a significant difference between analgesic requirements between groups M and F (p < 0.05). In both treatment groups pain scores of all three scales decreased over time. Results of the different pain scales correlated moderately to strongly. Utilising von Frey Filaments, results for skin sensitivity showed large individual variation, with a tendency towards reaction only at thicker filaments. Conclusion Subcutaneously methadone or transdermal fentanyl can provide adequate postoperative analgesia in dogs after spinal surgery without an intravenous catheter. The CMPS-SF and the CPS could reliably be used in this category of animal. Glasgow composite measure pain scale – short form (CMPS-SF) Colorado State University canine acute pain scale (CPS) visual analogue scale pain spinal surgery Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Thoracolumbar disc disease is a common neurological disease in dogs( 1 ). The postoperative analgesic treatment of these patients might be challenging, as their pain can include neuropathic, inflammatory and nociceptive components ( 2 ). Different strategies for analgesia post spinal surgery in dogs are reported, which are often based on multimodal analgesic treatments including local anaesthetic techniques and opioids ( 3 – 6 ). Methadone might have advantages because of interaction with NMDA receptors in addition to opioid receptors ( 7 ). Dogs after spinal surgery often require early physiotherapy and water treadmill exercise, which hinders or interferes with hygienic maintenance of an intravenous catheter. Unfortunately, methadone has very low oral bioavailability in dogs, necessitating parenteral drug application. Dosing regimens using intravenous methadone are documented, but due to the rather short half-life (3.9 ± 1.0 h), dosing every 4–6 hours would be required ( 8 ). A possibility to overcome some of these challenges could be subcutaneous (SC) application of methadone, as the half-life is longer (10.7 ± 4.3 h), so likely administration every 6 or even 12 hours could be adequate and no intravenous catheter would be needed( 8 ). At present, one study applying 0.25 mg/kg or 0.5 mg/kg SC methadone in premedication and 4 hours later for tibia plateau levelling osteotomy could demonstrate analgesia lasting up to 12 hours after first drug application in both treatment groups ( 9 ). Another option to provide postoperative opioid analgesia to dogs without the necessity to maintain an intravenous catheter is the transdermal route. A spot on fentanyl solution for dogs was available for a while, which had proven to be effective following a variety of soft tissue and orthopaedic surgeries ( 10 ). Several composite pain scales to evaluate postoperative pain behaviour in dogs exist( 11 – 13 ). Sensory alterations can be quantified by methods like testing of skin sensitivity or mechanical or thermal thresholds and seem to be more popular in studies than in clinical settings( 14 , 15 ). However, as pain scales focus on assessment of behavioural-based end points and the emotional part of pain, whereas stimulation tests rather evaluate the sensory part of the pain experience, a combination of techniques might be favourable in dogs with neurological disease. At present, no data are available to clearly recommend one pain type or sensation recognition tool or technique after spinal surgery over others. Therefore, the primary aim of this study was to evaluate if, subcutaneously applied methadone or transdermal fentanyl can offer sufficient postoperative analgesia in dogs after thoracolumbar neurosurgery without the necessity of keeping an intravenous access. A secondary aim was to evaluate which type of pain recognition tool/ technique or combination would be suitable in dogs with thoracolumbar disc disease in a clinical setting, as at present no specific pain scale for evaluating dogs after neurosurgery is available. The hypothesis is that subcutaneously applied methadone will provide adequate pain relieve in dogs after thoracolumbar spinal surgery. Results Demographic data were not different between treatment groups (Table 1 ). Table 1 Demographic data of 50 dogs included in the present study Treatment group Methadone Fentanyl Number of dogs (n) 25 25 Female (intact/spayed) 10 (5/5) 10 (0/10) Male (intact/castrated) 15 (10/5) 15 (14/1) Weight (kg) 12.6 ± 10.6 12.6 ± 7.8 Age (years) 6.7 ± 3.2 5.8 ± 2.2 Dachshound (11/25) (10/25) Mixed breed (1/25) (8/25) Beagle (1/25) (2/25) Jack Russel Terrier (2/25) (0/25) Bolonka Zwetna (1/25) (0/25) Dog de Bordeaux (1/25) (0/25) Border Collie (1/25) (0/25) Chihuahua (1/25) (0/25) Cocker Spaniel (0/25) (1/25) Coton de Tulear (0/25) (1/25) German shepherd (1/25) (0/25) English Bulldog (0/25) (1/25) French Bulldog (1/25) (0/25) Harzer Fuchs (1/25) (0/25) Havaneser (0/25) (1/25) Malinois (0/25) (1/25) Malteser (1/25) (0/25) Pekinese (1/25) (0/25) Shih Tzu (1/25) (0/25) At no time point, any of the used methods could demonstrate a significant difference between analgesic requirements between group methadone (M) and group fentanyl (F) (p 2, which resulted in evaluation of these 4 dogs 2 hours later at time point 4 hours. Rescue analgesia was required by 1/ 25 dog in M and 3/ 25 dogs in F. Six further dogs in M were scored ≥ 5 using the CMPS-SF, but showed clearly dysphoric behaviour (e.g. howling) which could not be interrupted by talking to the animal or approaching it. Therefore, no rescue analgesia was provided to these dogs and the methadone dose was reduced. In both treatment groups pain scores of all three scales decreased over time (Fig. 1 ; Fig. 2 ; Fig. 3 ). Results of the different pain scales correlated moderately to strongly (Table 2 ). Table 2 Spearman correlation between three pain scales: visual analogue scale (VAS), Glasgow Composite Measure Pain Scale – short form (CMPS-SF) and Colorado State University pain scale (CPS) for treatment groups methadone and fentanyl. Values between 0.5 and 0.75 indicate moderate correlation; values above 0.75 indicate strong correlation. Methadone Fentanyl p CMPS-SF vs CPS 0.70 0.73 < 0.001 CMPS-SF vs VAS 0.60 0.64 < 0.001 CPS vs VAS 0.62 0.70 < 0.001 Using the outcome-based measure: “is further analgesic treatment needed or not”, in both treatment groups a very strong agreement between CMPS-SF and CPS was demonstrated. For M and F, the prevalence and bias adjusted kappa coefficient were 0.86 and 0.93, respectively. Both scales lead to the same therapeutic decision in 215/ 231 (M) or 207/ 216 (F) measurements. Detailed results for the outcome-based measure are shown in Table 3 . Table 3 Outcome-based measure for the Glasgow Composite Measure Pain Scale – short form (CMPS-SF) and the Colorado State University pain scale (CPS) for treatment groups fentanyl and methadone. ≥ 5 or ≥ 4 indicating a need for further analgesia, < 5 or < 4 indicating an adequate pain state, according to the used pain scale. Methadone Fentanyl CMPS-SF < 5 ≥ 5 < 5 ≥ 5 CPS < 4 208 5 203 1 ≥ 4 11 7 6 4 Utilising von Frey Filaments, no significant difference in skin sensitivity could be detected between M and F. Results for skin sensitivity showed large individual variation, with a tendency towards reaction only at thicker filaments. Over all measurements, in 15% no positive reaction was visible, and in further 26% filaments larger than 100 g were needed (Fig. 4 ). Two dogs in F were bradycardic (40–48 bpm) and hypothermic (34.8°C), they received 0.01 mg/kg glycopyrrolium IM, active warming and an intravenous fluid therapy using a balanced electrolyte maintenance solution. Two dogs in M showed increased salivation, two dogs in each treatment group demonstrated one episode of vomitus and one dog in each treatment group developed diarrhoea, all of these gastrointestinal effects were self-limiting and did not require medical treatment. Discussion The hypothesis, that subcutaneous applied methadone can provide adequate postoperative analgesia in dogs after thoracolumbar neurosurgery could be confirmed. All three utilised pain scales provided reasonable monitoring of the animals. In contrast, von Frey Filament testing did not appear helpful for clinical evaluation of these dogs. Based on the low number of animals requiring rescue analgesia or showing undesirable effects both analgesic courses (SC methadone and transdermal fentanyl) appear clinically comparable and adequate. Both drugs are µ-, κ- and δ- opioid receptor agonists ( 16 , 17 ). They are therefore being classified as strong analgesics, which could be one explanation for their equal effectiveness. However, based on in vitro studies, for both methadone isomers dose-depending binding and antagonism at the NMDA-receptor is being discussed ( 18 , 19 ), which theoretically could have been beneficial in dogs with spinal disease. However, using the described doses, in the studied clinical cases no benefit of the possible NMDA action was detectable. In addition, an antihyperalgesic effect of the D- isomer of methadone is documented in laboratory rodents( 20 ). Using von Frey Filament testing, this could not be reproduced in this study with racemic methadone in dogs. Further, the application of pregabalin to all dogs could have attenuated smaller differences between treatment groups M and F. Including pregabalin in the postoperative analgesic plan for dogs with disc herniation, leads to favourable analgesia shown with reduced pain scores compared to methadone alone ( 15 ). Whereas only tendencies for lower pain scores are documented when gabapentin is used in a similar setting ( 21 ). Also in humans, pregabalin is known to be effective in patients suffering from varying diseases leading to neuropathic pain ( 22 , 23 ). Further an opioid sparing effects of pregabalin could be documented in humans and laboratory rodents ( 24 , 25 ). At present no data concerning opioid sparing in dogs exist, but plasma levels in dogs documented after 4 mg/kg orally applied pregabalin are in the range for which analgesia in humans is expected ( 26 ). The subcutaneous route for methadone application was chosen. At present, most postoperative analgesic plans including methadone use intravenous drug administration( 27 , 28 ). Literature about subcutaneous use of methadone in dogs is limited ( 9 , 29 , 30 ). Dosing regimens and duration of treatment in these studies are diverse. Based on pharmacokinetic data in dogs, indicating a longer half-life of methadone when injected subcutaneously than intravenously a treatment of four times daily was scheduled( 8 ) for the current trial. Judged on the low need of rescue analgesia in the present study this dosing regimen seems to be adequate for dogs after neurosurgery. Even though not evaluated here, a reduced treatment frequency might reduce stress/ discomfort of patient due to reduced handling and might increase compliance for treatment in a busy clinical team. Furthermore, subcutaneous drug administration avoids the necessity of keeping a patent intravenous catheter in non-ambulatory dogs. This also could be avoided using the transdermal fentanyl solution, which did prove to be effective and safe for the patient studied in the current trial. But, this fentanyl solution has been withdrawn from the marked between the execution of the clinical trial and manuscript preparation and is currently (2024) not available. Methadone was applied four times daily over the study course independently of pain scores of the animal. This alteration to clinical practice was taken to enable comparison to the long-acting transdermal fentanyl solution over the whole time of study. Therefore, the individual lowest effective dose was not titrated and it might be, that some dogs in M received more methadone than they would have needed based on pain scoring. Nevertheless, as only in a very low number of dogs in group M mild unwanted effects were present, the protocol of four times daily subcutaneous methadone seems to be suitable and safe in dogs after thoracolumbar spinal surgery. At present no specific pain scale for evaluating dogs after neurosurgery is available, therefore three different scales for measurement of acute postoperative pain were applied and compared. All three scales were able to detect post operative pain behaviour, but correlation between the two composite pain scales (CMPS-SF and CPS) was higher than with the VAS. The VAS is considered to be an unidimensional scale, based on the subjective impression of pain of the investigator ( 11 , 12 ). Hence giving a very individual impression of the multimodal nature of pain. Both composite scales include roughly three categories of evaluation: a) observation of demeanour and posture b) approach to the animal and interaction C) touching the animal/ painful area ( 31 ). Following the steps of the scales the observer is guided how to evaluate possible pain and therefore more aspects of pain behaviour are incorporated into the judgement in a structured way. This could explain why the composite scales correlate with each other more than with the VAS. Despite some differences in wording and the exact aspects which are evaluated, CMPS-SF and CPS agreed concerning the outcome-based measure “is rescue analgesia or more analgesia needed?” in 95% of all measurements. Considering the different intentions the scales were built for, this might be of particular interest for institutions regularly working with untrained persons ([nurse] students, young vets and nurse). The CMPS-FS was designed as a clinical decision making tool, helping, together with the clinical judgement, to decide if an alteration in analgesic treatment is necessary ( 13 ). In contrast, the CPS which includes more visual aids was created as a teaching tool, helping veterinary students to identify behaviours, which could be caused by pain ( 32 ). Keeping in mind, that in the present study dogs were evaluated by a single person with moderate experience, both composite scales seem to reliably detect pain after neurosurgery and likely could be used interchangeably in these cases. Using the scale, which fits best the clinical situation (e.g. Teaching hospital or not) therefore seems reasonable. Von Frey Filaments were used to include a way of accessing dermal sensitivity and presence of possible hypo- or hyperaesthesia into the present study. The filament at which dogs responded showed high variability. About 40% of the dogs responded only at one of the thickest filaments, or not at all. No distinct reason for this late reaction can be given. Dissection of nerves in the field of surgery could be one explanation, but using skin or skin and muscle incisions together with von Frey Filament application is an established model to evaluate postoperative analgesia and usually a decrease in reaction threshold is expected ( 33 – 35 ). In addition, dermatomes are often overlapping, therefore cutting the skin branch of single spinal nerves should not result in increased thresholds ( 36 ). Despite the absence of statistical significances, a trend towards increasing sensitivity towards the end of the observation period was visible in the current study. The reason for this is not clear, but it might indicate returning skin sensitivity. Further, classical von Frey Monofilaments are used to detect changes as hyperalgesia, which might develop after an insult ( 37 ). Evaluating the dogs the first days after surgery it might be, that time was too short for hyperalgesia or allodynia to be present. Further, the drugs applied could have influenced results of von Frey filament testing. Using an electronic von Frey device an increase in thresholds after morphine application in dogs is documented ( 38 ). In addition to the µ-opioid effect methadone acts antagonistic at spinal NMDA receptors, which could lead to an antihyperalgesic effect ( 7 ). Also, for Pregabalin, which was applied to all animals in the present study, reducing effects for cold and mechanical hyperalgesia in dogs with syringomyelia, chiari-like malformation or intervertebral disc disease are demonstrated ( 14 , 15 ). Von Frey Filament testing was always last section in evaluating a dog. Therefore, it cannot be excluded that some kind of learning effect developed, leading to lower or later reactions of the dogs. Nevertheless, findings of the present study equal results in healthy dogs of ≤ 8 kg ( 39 ) which showed a response rate to von Frey filament application in the thoracolumbar region of 56% and a tendency towards reaction with thicker filaments. Together with the fact that no clear hints for the requirement of rescue analgesia could be drawn from the data of the von Frey filament tests, it is questionable if utilising a test for skin hyperaesthesia is a good choice to evaluate immediate postoperative analgesia. Maybe measurements of classical mechanical thresholds using algometry would have been more useful. The clinical nature of this trial causes some limitations of the study. Length of disease before consultation in the clinic was not standardised, therefore dogs with acute, subacute and chronic problems were included. This might have resulted in a heterogenous study population, but reflects the clinical situation. Further, dogs were enrolled independently of the analgesic treatment applied by the referring colleague. In addition, during the hospitalisation period all medication, beside analgesic therapy, was on discretion of the neurologist in charge and not standardised. As no differences between the treatment groups and the applicability of the pain scores could be demonstrated it is highly unlikely that other medications have influenced the study results meaningfully. All animals were evaluated by only one investigator, to reduce stress to the hospitalised dogs it was decided to refrain from examination by multiple raters. Conclusion Subcutaneously methadone or transdermal fentanyl can provide adequate postoperative analgesia in dogs after surgery for thoracolumbar disc disease without the need of keeping an intravenous catheter. Both, the CMPS-SF and the CPS could be reliably used in this category of animal after spinal surgery. Methods The study design was ethically reviewed and approved by the Lower Saxony State Office for Consumer Protection and Food Safety (LAVES), according to regulations of the German Animal Welfare Act (AZ: 13A383). The trial was designed as a prospective, randomised, clinical study with the investigator unaware of the opioid-analgesic treatment of the dogs during the whole study period. Randomisation was achieved using a commercially available website ( www.randomization.com ). Dogs were privately owned, regular patients of the hospital, a written informed owner consent was obtained before study enrolment. Inclusion criteria were: age > 12 month, thoracolumbar disc disease requiring hemilaminectomy. Exclusion criteria were: age < 12 month, highly aggressive demeanour, need for revision surgery during the first 4 days post initial surgery, known or suspected intolerance against one of the drugs used in the trial. Treatment group M received 0.4 mg/kg methadone subcutaneously (SC) two hours before start of surgery and following this every 6 hours. Treatment group F received a topical application of 2.6 mg/ kg transdermal – fentanyl, two hours before start of the surgery. Following the manufactures recommendation fentanyl was applied to the region of the neck using personal protection including glows, gown and googles. After fentanyl application, dogs were restricted gently for two minutes to prevent shaking and inadvertent spreading of the drug. Intravenous (IV) anaesthesia premedication consisted of 0.4 mg/ kg levomethadone in a fixed combination with fenpipramid (L-Polamivet, Intervet Deutschland GmbH, Unterschleißheim, Germany) and 0.5 mg/ kg diazepam (Diazepam ratiopharm, Ratiopharm, Ulm, Germany). Propofol (Narcofol, CP-Pharma, Burgdorf, Germany) IV dosed to effect was used for anaesthesia induction. After endotracheal intubation using an endotracheal tube with cuff, anaesthesia was maintained using isoflurane (Isofluran CP, CP-Phama, Burdorf, Germany) in oxygen, delivered using a circle breathing system. Electrocardiogramm, ocillometric blood pressure, percentage of oxygenated haemoglobin, pulse rate, respiratory rate, expiratory carbon dioxide and anaesthesia gases as well as body temperature were monitored using a multiparameter anaesthesia monitor. Postoperative analgesia contained the study drug (methadone or fentanyl) and 4 mg/ kg pregabalin (Lyrica, Pfizer Manufacturing Deutschland GmbH, Freiburg, Germany) given every 8 hours orally. Depending on pain scores and appearance of dysphoria rescue analgesia 0.2 mg/ kg methadone (Comfortan, CP-Pharma, Burgdorf, Germany) or 50 mg/ kg metamizol (Novacen, CP- Pharma GmbH, Burgdorf, Germany) IV was administered. All non-analgesic medical treatment was at the decision of the vet in charge, who was not involved in this trial. Two hours after the end of anaesthesia, a sedation score was determined. If this was ≤ 2, pain evaluation was initiated. If the dog was still sedated (score > 2), pain evaluation was started two hours later. After the initial pain assessment, measurements for the trial were repeated every 12 hours over the next four days. Skin sensitivity was tested using a set of classical von Frey Filaments in ascending order. The filaments were placed perpendicular to the skin and force was increased until either the dog showed a reaction (looking towards the filament, withdrawing from the filament) or the filament was maximally bent. In case a reaction was observed, the weight of the filament was noted and the von Frey Filament examination of this point was ended. If no reaction of the dog was visible, the next bigger filament was tested. A minimum time of 10 seconds was allowed between testing different filaments in one location. Measurement locations were bilaterally, 0.5cm, 5 cm and 10 cm lateral to the surgical wound at half the length of the wound. Pain evaluation included determination of the short form Glasgow Composite Pain Scale (CMPS-SF), the canine acute pain scale (Colorado State University [CPS]) and a visual analogue scale (VAS). All three pain scores were filled out as paper sheets. Within one animal, scores were always used in the same order. Between animals, the order of the three pain scales was randomised. Concerning the CMPS-SF section B was excluded, as dogs were not ambulatory without help. Abbreviations cm centimetre °C degree Celsius CMPS-SF Glasgow Composite Measure Pain Scale CPS Colorado State University pain scale F fentanyl fig. figure IV intravenous kg kilogram M methadone mg milligram n number of dogs NMDA N-Methyl-D-Aspartat SC subcutanous tab. Table VAS visual analogue scale Declarations Conflict of interest: None of the authors declares any conflict of interest regarding the results of the present study. Acknowledgement: Not applicable Funding: Not applicable Ethical declaration: The study design was ethically reviewed and approved by the Lower Saxony State Office for Consumer Protection and Food Safety (LAVES), according to regulations of the German Animal Welfare Act (AZ: 13A383). Consent to publish declaration: Not applicable Author Contribution SBRK, JT and AV: study planningAFS & AV: Data collection AFS,AV and SBRK: analysis of dataAFS writing of main manuscript text AFS & AV prepartion of figuresall authors reviewed the manuscript Data Availability Data is provided within the manuscript. References Bray JP, Burbidge HM. The canine intervertebral disk: part one: structure and function. J Am Anim Hosp Assoc. 1998;34(1):55–63. Aeschbacher G. Neuropharmacology. In: Jaggy A, editor. Small Animal Neurology. Volume 2. Schlütersche Verlagsgesellschaft mbH & Co KG; 2010. pp. 191–3. Degani M, Briganti A, Dupont J, Tutunaru A, Picavet PP, Bolen G, Sandersen C. Perioperative analgesic efficacy of lumbar erector spinae plane block in dogs undergoing hemilaminectomy: a randomized blinded clinical trial. Vet Anaesth Analg. 2024;51(2):181–9. Aprea F, Cherubini GB, Palus V, Vettorato E, Corletto F. Effect of extradurally administered morphine on postoperative analgesia in dogs undergoing surgery for thoracolumbar intervertebral disk extrusion. J Am Vet Med Assoc. 2012;241(6):754–9. McFadzean WJM, Macfarlane P, Granger N, Murrell JC. Influence of peri-incisional epaxial muscle infiltration with bupivacaine pre- or post-surgery on opioid administration in dogs undergoing thoraco-lumbar hemilaminectomy. Vet J. 2021;270:105622. Skelding AM, Valverde A, Kilburn G. Evaluation of the analgesic effect of fentanyl-ketamine and fentanyl-lidocaine constant rate infusions in isoflurane-anesthetized dogs undergoing thoracolumbar hemilaminectomy. Vet Anaesth Analg. 2021;48(3):407–14. Gorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett. 1997;223(1):5–8. Ingvast-Larsson C, Holgersson A, Bondesson U, Lagerstedt AS, Olsson K. Clinical pharmacology of methadone in dogs. Vet Anaesth Analg. 2010;37(1):48–56. Upchurch D, Lin KTT, KuKanich B. Two doses of subcutaneous methadone for postoperative analgesia in dogs undergoing tibial plateau levelling osteotomies. J Small Anim Pract. 2024;65(6):368–75. Linton DD, Wilson MG, Newbound GC, Freise KJ, Clark TP. The effectiveness of a long-acting transdermal fentanyl solution compared to buprenorphine for the control of postoperative pain in dogs in a randomized, multicentered clinical study. J Vet Pharmacol Ther. 2012;35(Suppl 2):53–64. Holton L, Reid J, Scott EM, Pawson P, Nolan A. Development of a behaviour-based scale to measure acute pain in dogs. Vet Rec. 2001;148(17):525–31. Holton LL, Scott EM, Nolan AM, Reid J, Welsh E, Flaherty D. Comparison of three methods used for assessment of pain in dogs. J Am Vet Med Assoc. 1998;212(1):61–6. Reid J, Nolan AM, Hughes J, Lascelles DX, Pawson PE, Scott EM. Development of the short-form Glasgow Composite Measure Pain Scale (CMPS-SF) and derivation of an analgesic intervention score. Anim Welf. 2007. Sanchis-Mora S, Chang YM, Abeyesinghe SM, Fisher A, Upton N, Volk HA, Pelligand L. Pregabalin for the treatment of syringomyelia-associated neuropathic pain in dogs: A randomised, placebo-controlled, double-masked clinical trial. Vet J. 2019;250:55–62. Schmierer PA, Tünsmeyer J, Tipold A, Hartnack-Wilhelm S, Lesczuk P, Kästner SBR. Randomized controlled trial of pregabalin for analgesia after surgical treatment of intervertebral disc disease in dogs. Vet Surg. 2020;49(5):905–13. Comer SD, Cahill CM, Fentanyl. Receptor pharmacology, abuse potential, and implications for treatment. Neurosci Biobehav Rev. 2019;106:49–57. Kristensen K, Christensen CB, Christrup LL. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci. 1995;56(2):Pl45–50. Matsui A, Williams JT. Activation of µ-opioid receptors and block of Kir3 potassium channels and NMDA receptor conductance by L- and D-methadone in rat locus coeruleus. Br J Pharmacol. 2010;161(6):1403–13. Levinstein MR, De Oliveira PA, Casajuana-Martin N, Quiroz C, Budinich RC, Rais R, et al. Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone. Mol Psychiatry. 2024;29(3):624–32. Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J Pharmacol Exp Ther. 1999;289(2):1048–53. Aghighi SA, Tipold A, Piechotta M, Lewczuk P, Kästner SB. Assessment of the effects of adjunctive gabapentin on postoperative pain after intervertebral disc surgery in dogs. Vet Anaesth Analg. 2012;39(6):636–46. Onakpoya IJ, Thomas ET, Lee JJ, Goldacre B, Heneghan CJ. Benefits and harms of pregabalin in the management of neuropathic pain: a rapid review and meta-analysis of randomised clinical trials. BMJ Open. 2019;9(1):e023600. Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev. 2019;1(1):Cd007076. Popa G, Mititelu Tartau L, Stoleriu I, Lupusoru RV, Lupusoru CE, Ochiuz L. The effect of pregabalin - codeine combination on partial sciatic nerve ligation - induced peripheral mononeuropathy in rats. J Physiol Pharmacol. 2016;67(3):465–9. Zhang J, Ho KY, Wang Y. Efficacy of pregabalin in acute postoperative pain: a meta-analysis. Br J Anaesth. 2011;106(4):454–62. Salazar V, Dewey CW, Schwark W, Badgley BL, Gleed RD, Horne W, Ludders JW. Pharmacokinetics of single-dose oral pregabalin administration in normal dogs. Vet Anaesth Analg. 2009;36(6):574–80. Amengual M, Leigh H, Rioja E. Postoperative respiratory effects of intravenous fentanyl compared to intravenous methadone in dogs following spinal surgery. Vet Anaesth Analg. 2017;44(5):1042–8. Gutiérrez-Bautista ÁJ, Morgaz J, Granados MDM, Gómez-Villamandos RJ, Dominguez JM, Fernandez-Sarmiento JA, et al. Evaluation and comparison of postoperative analgesic effects of dexketoprofen and methadone in dogs. Vet Anaesth Analg. 2018;45(6):820–30. Bieberly ZD, KuKanich B, KuKanich KS, Berke KA, Klocke EE, Upchurch DA et al. Long-acting injectable methadone (methadone-fluconazole) provides safe and effective postoperative analgesia in a randomized clinical trial for dogs undergoing soft tissue surgery. Am J Vet Res. 2022;83(8). KuKanich B, KuKanich K, Rankin DC, Upchurch DA, Comroe A, Crauer B, et al. Perioperative analgesia associated with oral administration of a novel methadone-fluconazole-naltrexone formulation in dogs undergoing routine ovariohysterectomy. Am J Vet Res. 2020;81(9):699–707. Monteiro BP, Lascelles BDX, Murrell J, Robertson S, Steagall PVM, Wright B. 2022 WSAVA guidelines for the recognition, assessment and treatment of pain. J Small Anim Pract. 2023;64(4):177–254. Mich PM, Hellyer PW, Kogan L, Schoenfeld-Tacher R. Effects of a pilot training program on veterinary students' pain knowledge, attitude, and assessment skills. J Vet Med Educ. 2010;37(4):358–68. Choi GJ, Ahn EJ, Lee OH, Kang H. Effects of a BMI1008 mixture on postoperative pain in a rat model of incisional pain. PLoS ONE. 2021;16(9):e0257267. Castel D, Sabbag I, Meilin S. The effect of local/topical analgesics on incisional pain in a pig model. J Pain Res. 2017;10:2169–75. Jung YH, Kim H, Kim H, Kim E, Baik J, Kang H. The anti-nociceptive effect of BPC-157 on the incisional pain model in rats. J Dent Anesth Pain Med. 2022;22(2):97–105. Böhme G. Rückenmarksnerven. In: R Nickel AS, E Seiferle, editor. Lehrbuch der Anatomie der Haustiere Band IV Nervensystem, Sinnesorgane, Endokrine Drüsen. 4: Parey; 2004. pp. 389 – 98. DeLeo JA, Tanga FY, Tawfik VL. Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. Neuroscientist. 2004;10(1):40–52. KuKanich B, Lascelles BDX, Papich MG. Assessment of a von Frey device for evaluation of the antinociceptive effects of morphine and its application in pharmacodynamic modeling of morphine in dogs. Am J Vet Res. 2005;66(9):1616–22. Sanchis-Mora S, Chang YM, Abeyesinghe S, Fisher A, Volk HA, Pelligand L. Development and initial validation of a sensory threshold examination protocol (STEP) for phenotyping canine pain syndromes. Vet Anaesth Analg. 2017;44(3):600–14. Byrt T, Bishop J, Carlin JB. Bias, prevalence and kappa. J Clin Epidemiol. 1993;46(5):423–9. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 03 Oct, 2025 Read the published version in BMC Veterinary Research → Version 1 posted Editorial decision: Revision requested 13 May, 2025 Reviews received at journal 03 May, 2025 Reviews received at journal 29 Apr, 2025 Reviewers agreed at journal 28 Apr, 2025 Reviewers agreed at journal 26 Apr, 2025 Reviewers agreed at journal 26 Apr, 2025 Reviewers invited by journal 19 Mar, 2025 Editor assigned by journal 19 Mar, 2025 Editor invited by journal 18 Mar, 2025 Submission checks completed at journal 18 Mar, 2025 First submitted to journal 18 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6201354","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":432365117,"identity":"f148df86-baf6-49da-8c18-619b83bff033","order_by":0,"name":"Alexandra F Schütter","email":"data:image/png;base64,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","orcid":"","institution":"University of Veterinary Medicine Hannover, Foundation","correspondingAuthor":true,"prefix":"","firstName":"Alexandra","middleName":"F","lastName":"Schütter","suffix":""},{"id":432365121,"identity":"a8358664-f679-4fb6-89e4-3df4ceefc013","order_by":1,"name":"Anika Verhoeven","email":"","orcid":"","institution":"University of Veterinary Medicine Hannover, Foundation","correspondingAuthor":false,"prefix":"","firstName":"Anika","middleName":"","lastName":"Verhoeven","suffix":""},{"id":432365122,"identity":"d5ee3375-1295-43f8-8706-f3af4a892a31","order_by":2,"name":"Julia Tünsmeier","email":"","orcid":"","institution":"University of Veterinary Medicine Hannover, Foundation","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"","lastName":"Tünsmeier","suffix":""},{"id":432365123,"identity":"f163342a-aa9e-465f-9a3c-af044b8daac4","order_by":3,"name":"Sabine BR Kästner","email":"","orcid":"","institution":"University of Veterinary Medicine Hannover, Foundation","correspondingAuthor":false,"prefix":"","firstName":"Sabine","middleName":"BR","lastName":"Kästner","suffix":""}],"badges":[],"createdAt":"2025-03-11 08:38:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6201354/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6201354/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12917-025-04941-3","type":"published","date":"2025-10-03T15:58:08+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79173872,"identity":"2bbec868-87ec-4de9-a189-756eaa98d654","added_by":"auto","created_at":"2025-03-25 09:48:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":77561,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGlasgow composite measure pain scale – short form (CMPS-SF) over time for 25 dogs in group methadone (M) and 25 dogs in group fentanyl (F). Boxes contain 50% of data, the horizontal line within the box indicates the median, whiskers indicate minimum and maximum values. Significant differences to the first measurement point (2h or 4h postoperatively) within each treatment group are indicated with an asterisk (*). Measurements at time point 4h were only performed, if the dogs were too sedated at time point 2h to be evaluated.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6201354/v1/ebf88cd6da29a8bed11ff262.jpg"},{"id":79172470,"identity":"f3a5f01c-7271-4039-887b-a2a991b5801b","added_by":"auto","created_at":"2025-03-25 09:40:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":72610,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eColorado State University canine acute pain scale (CPS) over time for 25 dogs in group methadone (M) and 25 dogs in group fentanyl (F). Boxes contain 50% of data, the horizontal line within the box indicates the median, whiskers indicate minimum and maximum values. Significant differences to the first measurement point (2h or 4h postoperatively) within each treatment group are indicated with an asterisk (*). Measurements at time point 4h were only performed, if the dogs were too sedated at time point 2h to be evaluated.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6201354/v1/4b5528f8903593c3abb0fbfd.jpg"},{"id":79172471,"identity":"88d3ac7d-df0d-43ac-b312-9059e5a7a215","added_by":"auto","created_at":"2025-03-25 09:40:52","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":70220,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eVisual analogue scale (VAS) over time for 25 dogs in group methadone (M) and 25 dogs in group fentanyl (F). Boxes contain 50% of data, the horizontal line within the box indicates the median, whiskers indicate minimum and maximum values. Significant differences to the first measurement point (2h or 4h postoperatively) within each treatment group are indicated with an asterisk (*). Measurements at time point 4h were only performed, if the dogs were too sedated at time point 2h to be evaluated.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6201354/v1/b3769348693e3846ab59a4f7.jpg"},{"id":79172473,"identity":"1c409113-d51a-4ae4-9f07-499c10bc621a","added_by":"auto","created_at":"2025-03-25 09:40:52","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":276081,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eUsed von Frey Filaments used over time for 25 dogs in group methadone (M) (dark blue) and 25 dogs in group fentanyl (F) (light blue). Reactions left and right body side at 0.5, 5 and 10cm distance to the surgical wound are shown. Boxes contain 50% of data, the horizontal line within the box indicates the median, whiskers indicate minimum and maximum values. For animals not reacting at all, 1000g was set arbitrary to display this dogs in the figure.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6201354/v1/8dafcc0b54236bc8b9295e82.jpg"},{"id":92883819,"identity":"2906982c-084d-428a-acb9-d865cef689d0","added_by":"auto","created_at":"2025-10-06 16:10:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1780085,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6201354/v1/f7cbcf24-ae3b-4b91-8da0-4b9b028e0d8f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Subcutaneous methadone is not different than transdermal fentanyl for postoperative analgesia in dogs with thoracolumbar disc disease, using three different pain scales and von Frey Filaments, a prospective, randomised, blinded clinical study","fulltext":[{"header":"Background","content":"\u003cp\u003eThoracolumbar disc disease is a common neurological disease in dogs(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The postoperative analgesic treatment of these patients might be challenging, as their pain can include neuropathic, inflammatory and nociceptive components (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Different strategies for analgesia post spinal surgery in dogs are reported, which are often based on multimodal analgesic treatments including local anaesthetic techniques and opioids (\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Methadone might have advantages because of interaction with NMDA receptors in addition to opioid receptors (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Dogs after spinal surgery often require early physiotherapy and water treadmill exercise, which hinders or interferes with hygienic maintenance of an intravenous catheter. Unfortunately, methadone has very low oral bioavailability in dogs, necessitating parenteral drug application. Dosing regimens using intravenous methadone are documented, but due to the rather short half-life (3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0 h), dosing every 4\u0026ndash;6 hours would be required (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). A possibility to overcome some of these challenges could be subcutaneous (SC) application of methadone, as the half-life is longer (10.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 h), so likely administration every 6 or even 12 hours could be adequate and no intravenous catheter would be needed(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). At present, one study applying 0.25 mg/kg or 0.5 mg/kg SC methadone in premedication and 4 hours later for tibia plateau levelling osteotomy could demonstrate analgesia lasting up to 12 hours after first drug application in both treatment groups (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnother option to provide postoperative opioid analgesia to dogs without the necessity to maintain an intravenous catheter is the transdermal route. A spot on fentanyl solution for dogs was available for a while, which had proven to be effective following a variety of soft tissue and orthopaedic surgeries (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSeveral composite pain scales to evaluate postoperative pain behaviour in dogs exist(\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Sensory alterations can be quantified by methods like testing of skin sensitivity or mechanical or thermal thresholds and seem to be more popular in studies than in clinical settings(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). However, as pain scales focus on assessment of behavioural-based end points and the emotional part of pain, whereas stimulation tests rather evaluate the sensory part of the pain experience, a combination of techniques might be favourable in dogs with neurological disease. At present, no data are available to clearly recommend one pain type or sensation recognition tool or technique after spinal surgery over others.\u003c/p\u003e \u003cp\u003eTherefore, the primary aim of this study was to evaluate if, subcutaneously applied methadone or transdermal fentanyl can offer sufficient postoperative analgesia in dogs after thoracolumbar neurosurgery without the necessity of keeping an intravenous access. A secondary aim was to evaluate which type of pain recognition tool/ technique or combination would be suitable in dogs with thoracolumbar disc disease in a clinical setting, as at present no specific pain scale for evaluating dogs after neurosurgery is available.\u003c/p\u003e \u003cp\u003eThe hypothesis is that subcutaneously applied methadone will provide adequate pain relieve in dogs after thoracolumbar spinal surgery.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDemographic data were not different between treatment groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic data of 50 dogs included in the present study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMethadone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFentanyl\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of dogs (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale (intact/spayed)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (5/5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (0/10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale (intact/castrated)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (10/5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (14/1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDachshound\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(11/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(10/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed breed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(8/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBeagle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(2/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJack Russel Terrier\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(2/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBolonka Zwetna\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDog de Bordeaux\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBorder Collie\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChihuahua\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCocker Spaniel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoton de Tulear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGerman shepherd\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnglish Bulldog\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrench Bulldog\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHarzer Fuchs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHavaneser\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalinois\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalteser\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePekinese\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShih Tzu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAt no time point, any of the used methods could demonstrate a significant difference between analgesic requirements between group methadone (M) and group fentanyl (F) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). At time point 2 hour 4 dogs in F showed a sedation score\u0026thinsp;\u0026gt;\u0026thinsp;2, which resulted in evaluation of these 4 dogs 2 hours later at time point 4 hours.\u003c/p\u003e \u003cp\u003eRescue analgesia was required by 1/ 25 dog in M and 3/ 25 dogs in F. Six further dogs in M were scored\u0026thinsp;\u0026ge;\u0026thinsp;5 using the CMPS-SF, but showed clearly dysphoric behaviour (e.g. howling) which could not be interrupted by talking to the animal or approaching it. Therefore, no rescue analgesia was provided to these dogs and the methadone dose was reduced.\u003c/p\u003e \u003cp\u003eIn both treatment groups pain scores of all three scales decreased over time (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Results of the different pain scales correlated moderately to strongly (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSpearman correlation between three pain scales: visual analogue scale (VAS), Glasgow Composite Measure Pain Scale \u0026ndash; short form (CMPS-SF) and Colorado State University pain scale (CPS) for treatment groups methadone and fentanyl. Values between 0.5 and 0.75 indicate moderate correlation; values above 0.75 indicate strong correlation.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMethadone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFentanyl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMPS-SF vs CPS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMPS-SF vs VAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPS vs VAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eUsing the outcome-based measure: \u0026ldquo;is further analgesic treatment needed or not\u0026rdquo;, in both treatment groups a very strong agreement between CMPS-SF and CPS was demonstrated. For M and F, the prevalence and bias adjusted kappa coefficient were 0.86 and 0.93, respectively. Both scales lead to the same therapeutic decision in 215/ 231 (M) or 207/ 216 (F) measurements. Detailed results for the outcome-based measure are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOutcome-based measure for the Glasgow Composite Measure Pain Scale \u0026ndash; short form (CMPS-SF) and the Colorado State University pain scale (CPS) for treatment groups fentanyl and methadone. \u0026ge; 5 or \u0026ge;\u0026thinsp;4 indicating a need for further analgesia, \u0026lt; 5 or \u0026lt;\u0026thinsp;4 indicating an adequate pain state, according to the used pain scale.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"2\" nameend=\"c2\" namest=\"c1\" rowspan=\"3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eMethadone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eFentanyl\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e \u003cp\u003eCMPS-SF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCPS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eUtilising von Frey Filaments, no significant difference in skin sensitivity could be detected between M and F. Results for skin sensitivity showed large individual variation, with a tendency towards reaction only at thicker filaments. Over all measurements, in 15% no positive reaction was visible, and in further 26% filaments larger than 100 g were needed (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTwo dogs in F were bradycardic (40\u0026ndash;48 bpm) and hypothermic (34.8\u0026deg;C), they received 0.01 mg/kg glycopyrrolium IM, active warming and an intravenous fluid therapy using a balanced electrolyte maintenance solution.\u003c/p\u003e \u003cp\u003eTwo dogs in M showed increased salivation, two dogs in each treatment group demonstrated one episode of vomitus and one dog in each treatment group developed diarrhoea, all of these gastrointestinal effects were self-limiting and did not require medical treatment.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe hypothesis, that subcutaneous applied methadone can provide adequate postoperative analgesia in dogs after thoracolumbar neurosurgery could be confirmed. All three utilised pain scales provided reasonable monitoring of the animals. In contrast, von Frey Filament testing did not appear helpful for clinical evaluation of these dogs.\u003c/p\u003e \u003cp\u003eBased on the low number of animals requiring rescue analgesia or showing undesirable effects both analgesic courses (SC methadone and transdermal fentanyl) appear clinically comparable and adequate. Both drugs are \u0026micro;-, κ- and δ- opioid receptor agonists (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). They are therefore being classified as strong analgesics, which could be one explanation for their equal effectiveness. However, based on in vitro studies, for both methadone isomers dose-depending binding and antagonism at the NMDA-receptor is being discussed (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), which theoretically could have been beneficial in dogs with spinal disease. However, using the described doses, in the studied clinical cases no benefit of the possible NMDA action was detectable. In addition, an antihyperalgesic effect of the D- isomer of methadone is documented in laboratory rodents(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Using von Frey Filament testing, this could not be reproduced in this study with racemic methadone in dogs.\u003c/p\u003e \u003cp\u003eFurther, the application of pregabalin to all dogs could have attenuated smaller differences between treatment groups M and F. Including pregabalin in the postoperative analgesic plan for dogs with disc herniation, leads to favourable analgesia shown with reduced pain scores compared to methadone alone (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Whereas only tendencies for lower pain scores are documented when gabapentin is used in a similar setting (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Also in humans, pregabalin is known to be effective in patients suffering from varying diseases leading to neuropathic pain (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Further an opioid sparing effects of pregabalin could be documented in humans and laboratory rodents (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). At present no data concerning opioid sparing in dogs exist, but plasma levels in dogs documented after 4 mg/kg orally applied pregabalin are in the range for which analgesia in humans is expected (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe subcutaneous route for methadone application was chosen. At present, most postoperative analgesic plans including methadone use intravenous drug administration(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Literature about subcutaneous use of methadone in dogs is limited (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Dosing regimens and duration of treatment in these studies are diverse. Based on pharmacokinetic data in dogs, indicating a longer half-life of methadone when injected subcutaneously than intravenously a treatment of four times daily was scheduled(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) for the current trial. Judged on the low need of rescue analgesia in the present study this dosing regimen seems to be adequate for dogs after neurosurgery. Even though not evaluated here, a reduced treatment frequency might reduce stress/ discomfort of patient due to reduced handling and might increase compliance for treatment in a busy clinical team. Furthermore, subcutaneous drug administration avoids the necessity of keeping a patent intravenous catheter in non-ambulatory dogs. This also could be avoided using the transdermal fentanyl solution, which did prove to be effective and safe for the patient studied in the current trial. But, this fentanyl solution has been withdrawn from the marked between the execution of the clinical trial and manuscript preparation and is currently (2024) not available.\u003c/p\u003e \u003cp\u003eMethadone was applied four times daily over the study course independently of pain scores of the animal. This alteration to clinical practice was taken to enable comparison to the long-acting transdermal fentanyl solution over the whole time of study. Therefore, the individual lowest effective dose was not titrated and it might be, that some dogs in M received more methadone than they would have needed based on pain scoring. Nevertheless, as only in a very low number of dogs in group M mild unwanted effects were present, the protocol of four times daily subcutaneous methadone seems to be suitable and safe in dogs after thoracolumbar spinal surgery.\u003c/p\u003e \u003cp\u003eAt present no specific pain scale for evaluating dogs after neurosurgery is available, therefore three different scales for measurement of acute postoperative pain were applied and compared. All three scales were able to detect post operative pain behaviour, but correlation between the two composite pain scales (CMPS-SF and CPS) was higher than with the VAS. The VAS is considered to be an unidimensional scale, based on the subjective impression of pain of the investigator (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Hence giving a very individual impression of the multimodal nature of pain. Both composite scales include roughly three categories of evaluation: a) observation of demeanour and posture b) approach to the animal and interaction C) touching the animal/ painful area (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Following the steps of the scales the observer is guided how to evaluate possible pain and therefore more aspects of pain behaviour are incorporated into the judgement in a structured way. This could explain why the composite scales correlate with each other more than with the VAS. Despite some differences in wording and the exact aspects which are evaluated, CMPS-SF and CPS agreed concerning the outcome-based measure \u0026ldquo;is rescue analgesia or more analgesia needed?\u0026rdquo; in 95% of all measurements. Considering the different intentions the scales were built for, this might be of particular interest for institutions regularly working with untrained persons ([nurse] students, young vets and nurse). The CMPS-FS was designed as a clinical decision making tool, helping, together with the clinical judgement, to decide if an alteration in analgesic treatment is necessary (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In contrast, the CPS which includes more visual aids was created as a teaching tool, helping veterinary students to identify behaviours, which could be caused by pain (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Keeping in mind, that in the present study dogs were evaluated by a single person with moderate experience, both composite scales seem to reliably detect pain after neurosurgery and likely could be used interchangeably in these cases. Using the scale, which fits best the clinical situation (e.g. Teaching hospital or not) therefore seems reasonable.\u003c/p\u003e \u003cp\u003eVon Frey Filaments were used to include a way of accessing dermal sensitivity and presence of possible hypo- or hyperaesthesia into the present study. The filament at which dogs responded showed high variability. About 40% of the dogs responded only at one of the thickest filaments, or not at all.\u003c/p\u003e \u003cp\u003eNo distinct reason for this late reaction can be given. Dissection of nerves in the field of surgery could be one explanation, but using skin or skin and muscle incisions together with von Frey Filament application is an established model to evaluate postoperative analgesia and usually a decrease in reaction threshold is expected (\u003cspan additionalcitationids=\"CR34\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). In addition, dermatomes are often overlapping, therefore cutting the skin branch of single spinal nerves should not result in increased thresholds (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Despite the absence of statistical significances, a trend towards increasing sensitivity towards the end of the observation period was visible in the current study. The reason for this is not clear, but it might indicate returning skin sensitivity. Further, classical von Frey Monofilaments are used to detect changes as hyperalgesia, which might develop after an insult (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Evaluating the dogs the first days after surgery it might be, that time was too short for hyperalgesia or allodynia to be present. Further, the drugs applied could have influenced results of von Frey filament testing. Using an electronic von Frey device an increase in thresholds after morphine application in dogs is documented (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). In addition to the \u0026micro;-opioid effect methadone acts antagonistic at spinal NMDA receptors, which could lead to an antihyperalgesic effect (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Also, for Pregabalin, which was applied to all animals in the present study, reducing effects for cold and mechanical hyperalgesia in dogs with syringomyelia, chiari-like malformation or intervertebral disc disease are demonstrated (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Von Frey Filament testing was always last section in evaluating a dog. Therefore, it cannot be excluded that some kind of learning effect developed, leading to lower or later reactions of the dogs.\u003c/p\u003e \u003cp\u003eNevertheless, findings of the present study equal results in healthy dogs of \u0026le;\u0026thinsp;8 kg (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e) which showed a response rate to von Frey filament application in the thoracolumbar region of 56% and a tendency towards reaction with thicker filaments. Together with the fact that no clear hints for the requirement of rescue analgesia could be drawn from the data of the von Frey filament tests, it is questionable if utilising a test for skin hyperaesthesia is a good choice to evaluate immediate postoperative analgesia. Maybe measurements of classical mechanical thresholds using algometry would have been more useful.\u003c/p\u003e \u003cp\u003eThe clinical nature of this trial causes some limitations of the study. Length of disease before consultation in the clinic was not standardised, therefore dogs with acute, subacute and chronic problems were included. This might have resulted in a heterogenous study population, but reflects the clinical situation. Further, dogs were enrolled independently of the analgesic treatment applied by the referring colleague. In addition, during the hospitalisation period all medication, beside analgesic therapy, was on discretion of the neurologist in charge and not standardised. As no differences between the treatment groups and the applicability of the pain scores could be demonstrated it is highly unlikely that other medications have influenced the study results meaningfully.\u003c/p\u003e \u003cp\u003eAll animals were evaluated by only one investigator, to reduce stress to the hospitalised dogs it was decided to refrain from examination by multiple raters.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSubcutaneously methadone or transdermal fentanyl can provide adequate postoperative analgesia in dogs after surgery for thoracolumbar disc disease without the need of keeping an intravenous catheter. Both, the CMPS-SF and the CPS could be reliably used in this category of animal after spinal surgery.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe study design was ethically reviewed and approved by the Lower Saxony State Office for Consumer Protection and Food Safety (LAVES), according to regulations of the German Animal Welfare Act (AZ: 13A383).\u003c/p\u003e\n\u003cp\u003eThe trial was designed as a prospective, randomised, clinical study with the investigator unaware of the opioid-analgesic treatment of the dogs during the whole study period. Randomisation was achieved using a commercially available website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.randomization.com\u003c/span\u003e\u003c/span\u003e). Dogs were privately owned, regular patients of the hospital, a written informed owner consent was obtained before study enrolment. Inclusion criteria were: age\u0026thinsp;\u0026gt;\u0026thinsp;12 month, thoracolumbar disc disease requiring hemilaminectomy. Exclusion criteria were: age\u0026thinsp;\u0026lt;\u0026thinsp;12 month, highly aggressive demeanour, need for revision surgery during the first 4 days post initial surgery, known or suspected intolerance against one of the drugs used in the trial.\u003c/p\u003e\n\u003cp\u003eTreatment group M received 0.4 mg/kg methadone subcutaneously (SC) two hours before start of surgery and following this every 6 hours. Treatment group F received a topical application of 2.6 mg/ kg transdermal \u0026ndash; fentanyl, two hours before start of the surgery. Following the manufactures recommendation fentanyl was applied to the region of the neck using personal protection including glows, gown and googles. After fentanyl application, dogs were restricted gently for two minutes to prevent shaking and inadvertent spreading of the drug.\u003c/p\u003e\n\u003cp\u003eIntravenous (IV) anaesthesia premedication consisted of 0.4 mg/ kg levomethadone in a fixed combination with fenpipramid (L-Polamivet, Intervet Deutschland GmbH, Unterschlei\u0026szlig;heim, Germany) and 0.5 mg/ kg diazepam (Diazepam ratiopharm, Ratiopharm, Ulm, Germany). Propofol (Narcofol, CP-Pharma, Burgdorf, Germany) IV dosed to effect was used for anaesthesia induction. After endotracheal intubation using an endotracheal tube with cuff, anaesthesia was maintained using isoflurane (Isofluran CP, CP-Phama, Burdorf, Germany) in oxygen, delivered using a circle breathing system. Electrocardiogramm, ocillometric blood pressure, percentage of oxygenated haemoglobin, pulse rate, respiratory rate, expiratory carbon dioxide and anaesthesia gases as well as body temperature were monitored using a multiparameter anaesthesia monitor.\u003c/p\u003e\n\u003cp\u003ePostoperative analgesia contained the study drug (methadone or fentanyl) and 4 mg/ kg pregabalin (Lyrica, Pfizer Manufacturing Deutschland GmbH, Freiburg, Germany) given every 8 hours orally. Depending on pain scores and appearance of dysphoria rescue analgesia 0.2 mg/ kg methadone (Comfortan, CP-Pharma, Burgdorf, Germany) or 50 mg/ kg metamizol (Novacen, CP- Pharma GmbH, Burgdorf, Germany) IV was administered.\u003c/p\u003e\n\u003cp\u003eAll non-analgesic medical treatment was at the decision of the vet in charge, who was not involved in this trial.\u003c/p\u003e\n\u003cp\u003eTwo hours after the end of anaesthesia, a sedation score was determined. If this was \u0026le;\u0026thinsp;2, pain evaluation was initiated. If the dog was still sedated (score\u0026thinsp;\u0026gt;\u0026thinsp;2), pain evaluation was started two hours later. After the initial pain assessment, measurements for the trial were repeated every 12 hours over the next four days.\u003c/p\u003e\n\u003cp\u003eSkin sensitivity was tested using a set of classical von Frey Filaments in ascending order. The filaments were placed perpendicular to the skin and force was increased until either the dog showed a reaction (looking towards the filament, withdrawing from the filament) or the filament was maximally bent. In case a reaction was observed, the weight of the filament was noted and the von Frey Filament examination of this point was ended. If no reaction of the dog was visible, the next bigger filament was tested. A minimum time of 10 seconds was allowed between testing different filaments in one location. Measurement locations were bilaterally, 0.5cm, 5 cm and 10 cm lateral to the surgical wound at half the length of the wound.\u003c/p\u003e\n\u003cp\u003ePain evaluation included determination of the short form Glasgow Composite Pain Scale (CMPS-SF), the canine acute pain scale (Colorado State University [CPS]) and a visual analogue scale (VAS). All three pain scores were filled out as paper sheets. Within one animal, scores were always used in the same order. Between animals, the order of the three pain scales was randomised. Concerning the CMPS-SF section B was excluded, as dogs were not ambulatory without help.\u003c/p\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003cbr\u003e\u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ecm\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;centimetre\u003c/p\u003e\n\u003cp\u003e°C\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;degree Celsius\u003c/p\u003e\n\u003cp\u003eCMPS-SF\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Glasgow Composite Measure Pain Scale\u003c/p\u003e\n\u003cp\u003eCPS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Colorado State University pain scale\u003c/p\u003e\n\u003cp\u003eF\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;fentanyl\u003c/p\u003e\n\u003cp\u003efig. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;figure\u003c/p\u003e\n\u003cp\u003eIV\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;intravenous\u003c/p\u003e\n\u003cp\u003ekg\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;kilogram\u003c/p\u003e\n\u003cp\u003eM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;methadone\u003c/p\u003e\n\u003cp\u003emg\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;milligram\u003c/p\u003e\n\u003cp\u003en\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;number of dogs\u003c/p\u003e\n\u003cp\u003eNMDA\u0026nbsp;\u0026nbsp;N-Methyl-D-Aspartat\u003c/p\u003e\n\u003cp\u003eSC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;subcutanous\u003c/p\u003e\n\u003cp\u003etab.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Table\u003c/p\u003e\n\u003cp\u003eVAS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;visual analogue scale\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eConflict of interest:\u003c/p\u003e\n\u003cp\u003eNone of the authors declares any conflict of interest regarding the results of the present study.\u003c/p\u003e\n\u003cp\u003eAcknowledgement:\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eFunding:\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eEthical declaration:\u003c/p\u003e\n\u003cp\u003eThe study design was ethically reviewed and approved by the Lower Saxony State Office for Consumer Protection and Food Safety (LAVES), according to regulations of the German Animal Welfare Act (AZ: 13A383).\u003c/p\u003e\n\u003cp\u003eConsent to publish declaration:\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eAuthor Contribution\u003c/p\u003e\n\u003cp\u003eSBRK, JT and AV: study planningAFS \u0026amp; AV: Data collection AFS,AV and SBRK: analysis of dataAFS writing of main manuscript text AFS \u0026amp; AV prepartion of figuresall authors reviewed the manuscript\u003c/p\u003e\n\u003cp\u003eData Availability\u003c/p\u003e\n\u003cp\u003eData is provided within the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray JP, Burbidge HM. The canine intervertebral disk: part one: structure and function. J Am Anim Hosp Assoc. 1998;34(1):55\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAeschbacher G. Neuropharmacology. In: Jaggy A, editor. Small Animal Neurology. Volume 2. Schl\u0026uuml;tersche Verlagsgesellschaft mbH \u0026amp; Co KG; 2010. pp. 191\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDegani M, Briganti A, Dupont J, Tutunaru A, Picavet PP, Bolen G, Sandersen C. Perioperative analgesic efficacy of lumbar erector spinae plane block in dogs undergoing hemilaminectomy: a randomized blinded clinical trial. Vet Anaesth Analg. 2024;51(2):181\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAprea F, Cherubini GB, Palus V, Vettorato E, Corletto F. Effect of extradurally administered morphine on postoperative analgesia in dogs undergoing surgery for thoracolumbar intervertebral disk extrusion. J Am Vet Med Assoc. 2012;241(6):754\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcFadzean WJM, Macfarlane P, Granger N, Murrell JC. Influence of peri-incisional epaxial muscle infiltration with bupivacaine pre- or post-surgery on opioid administration in dogs undergoing thoraco-lumbar hemilaminectomy. Vet J. 2021;270:105622.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSkelding AM, Valverde A, Kilburn G. Evaluation of the analgesic effect of fentanyl-ketamine and fentanyl-lidocaine constant rate infusions in isoflurane-anesthetized dogs undergoing thoracolumbar hemilaminectomy. Vet Anaesth Analg. 2021;48(3):407\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett. 1997;223(1):5\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIngvast-Larsson C, Holgersson A, Bondesson U, Lagerstedt AS, Olsson K. Clinical pharmacology of methadone in dogs. Vet Anaesth Analg. 2010;37(1):48\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUpchurch D, Lin KTT, KuKanich B. Two doses of subcutaneous methadone for postoperative analgesia in dogs undergoing tibial plateau levelling osteotomies. J Small Anim Pract. 2024;65(6):368\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLinton DD, Wilson MG, Newbound GC, Freise KJ, Clark TP. The effectiveness of a long-acting transdermal fentanyl solution compared to buprenorphine for the control of postoperative pain in dogs in a randomized, multicentered clinical study. J Vet Pharmacol Ther. 2012;35(Suppl 2):53\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolton L, Reid J, Scott EM, Pawson P, Nolan A. Development of a behaviour-based scale to measure acute pain in dogs. Vet Rec. 2001;148(17):525\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolton LL, Scott EM, Nolan AM, Reid J, Welsh E, Flaherty D. Comparison of three methods used for assessment of pain in dogs. J Am Vet Med Assoc. 1998;212(1):61\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReid J, Nolan AM, Hughes J, Lascelles DX, Pawson PE, Scott EM. Development of the short-form Glasgow Composite Measure Pain Scale (CMPS-SF) and derivation of an analgesic intervention score. Anim Welf. 2007.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanchis-Mora S, Chang YM, Abeyesinghe SM, Fisher A, Upton N, Volk HA, Pelligand L. Pregabalin for the treatment of syringomyelia-associated neuropathic pain in dogs: A randomised, placebo-controlled, double-masked clinical trial. Vet J. 2019;250:55\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmierer PA, T\u0026uuml;nsmeyer J, Tipold A, Hartnack-Wilhelm S, Lesczuk P, K\u0026auml;stner SBR. Randomized controlled trial of pregabalin for analgesia after surgical treatment of intervertebral disc disease in dogs. Vet Surg. 2020;49(5):905\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eComer SD, Cahill CM, Fentanyl. Receptor pharmacology, abuse potential, and implications for treatment. Neurosci Biobehav Rev. 2019;106:49\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKristensen K, Christensen CB, Christrup LL. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci. 1995;56(2):Pl45\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsui A, Williams JT. Activation of \u0026micro;-opioid receptors and block of Kir3 potassium channels and NMDA receptor conductance by L- and D-methadone in rat locus coeruleus. Br J Pharmacol. 2010;161(6):1403\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevinstein MR, De Oliveira PA, Casajuana-Martin N, Quiroz C, Budinich RC, Rais R, et al. Unique pharmacodynamic properties and low abuse liability of the \u0026micro;-opioid receptor ligand (S)-methadone. Mol Psychiatry. 2024;29(3):624\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J Pharmacol Exp Ther. 1999;289(2):1048\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAghighi SA, Tipold A, Piechotta M, Lewczuk P, K\u0026auml;stner SB. Assessment of the effects of adjunctive gabapentin on postoperative pain after intervertebral disc surgery in dogs. Vet Anaesth Analg. 2012;39(6):636\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOnakpoya IJ, Thomas ET, Lee JJ, Goldacre B, Heneghan CJ. Benefits and harms of pregabalin in the management of neuropathic pain: a rapid review and meta-analysis of randomised clinical trials. BMJ Open. 2019;9(1):e023600.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDerry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev. 2019;1(1):Cd007076.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePopa G, Mititelu Tartau L, Stoleriu I, Lupusoru RV, Lupusoru CE, Ochiuz L. The effect of pregabalin - codeine combination on partial sciatic nerve ligation - induced peripheral mononeuropathy in rats. J Physiol Pharmacol. 2016;67(3):465\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang J, Ho KY, Wang Y. Efficacy of pregabalin in acute postoperative pain: a meta-analysis. Br J Anaesth. 2011;106(4):454\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalazar V, Dewey CW, Schwark W, Badgley BL, Gleed RD, Horne W, Ludders JW. Pharmacokinetics of single-dose oral pregabalin administration in normal dogs. Vet Anaesth Analg. 2009;36(6):574\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmengual M, Leigh H, Rioja E. Postoperative respiratory effects of intravenous fentanyl compared to intravenous methadone in dogs following spinal surgery. Vet Anaesth Analg. 2017;44(5):1042\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuti\u0026eacute;rrez-Bautista \u0026Aacute;J, Morgaz J, Granados MDM, G\u0026oacute;mez-Villamandos RJ, Dominguez JM, Fernandez-Sarmiento JA, et al. Evaluation and comparison of postoperative analgesic effects of dexketoprofen and methadone in dogs. Vet Anaesth Analg. 2018;45(6):820\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBieberly ZD, KuKanich B, KuKanich KS, Berke KA, Klocke EE, Upchurch DA et al. Long-acting injectable methadone (methadone-fluconazole) provides safe and effective postoperative analgesia in a randomized clinical trial for dogs undergoing soft tissue surgery. Am J Vet Res. 2022;83(8).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuKanich B, KuKanich K, Rankin DC, Upchurch DA, Comroe A, Crauer B, et al. Perioperative analgesia associated with oral administration of a novel methadone-fluconazole-naltrexone formulation in dogs undergoing routine ovariohysterectomy. Am J Vet Res. 2020;81(9):699\u0026ndash;707.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonteiro BP, Lascelles BDX, Murrell J, Robertson S, Steagall PVM, Wright B. 2022 WSAVA guidelines for the recognition, assessment and treatment of pain. J Small Anim Pract. 2023;64(4):177\u0026ndash;254.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMich PM, Hellyer PW, Kogan L, Schoenfeld-Tacher R. Effects of a pilot training program on veterinary students' pain knowledge, attitude, and assessment skills. J Vet Med Educ. 2010;37(4):358\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChoi GJ, Ahn EJ, Lee OH, Kang H. Effects of a BMI1008 mixture on postoperative pain in a rat model of incisional pain. PLoS ONE. 2021;16(9):e0257267.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCastel D, Sabbag I, Meilin S. The effect of local/topical analgesics on incisional pain in a pig model. J Pain Res. 2017;10:2169\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJung YH, Kim H, Kim H, Kim E, Baik J, Kang H. The anti-nociceptive effect of BPC-157 on the incisional pain model in rats. J Dent Anesth Pain Med. 2022;22(2):97\u0026ndash;105.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eB\u0026ouml;hme G. R\u0026uuml;ckenmarksnerven. In: R Nickel AS, E Seiferle, editor. Lehrbuch der Anatomie der Haustiere Band IV Nervensystem, Sinnesorgane, Endokrine Dr\u0026uuml;sen. 4: Parey; 2004. pp. 389\u0026thinsp;\u0026ndash;\u0026thinsp;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeLeo JA, Tanga FY, Tawfik VL. Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. Neuroscientist. 2004;10(1):40\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuKanich B, Lascelles BDX, Papich MG. Assessment of a von Frey device for evaluation of the antinociceptive effects of morphine and its application in pharmacodynamic modeling of morphine in dogs. Am J Vet Res. 2005;66(9):1616\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanchis-Mora S, Chang YM, Abeyesinghe S, Fisher A, Volk HA, Pelligand L. Development and initial validation of a sensory threshold examination protocol (STEP) for phenotyping canine pain syndromes. Vet Anaesth Analg. 2017;44(3):600\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eByrt T, Bishop J, Carlin JB. Bias, prevalence and kappa. J Clin Epidemiol. 1993;46(5):423\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-veterinary-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [BMC Veterinary Research](http://bmcvetres.biomedcentral.com/)","snPcode":"12917","submissionUrl":"https://submission.nature.com/new-submission/12917/3?","title":"BMC Veterinary Research","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Glasgow composite measure pain scale – short form (CMPS-SF), Colorado State University canine acute pain scale (CPS), visual analogue scale, pain, spinal surgery","lastPublishedDoi":"10.21203/rs.3.rs-6201354/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6201354/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eBackground\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThoracolumbar disc disease is a common neurological disease in dogs, which incorporated different pain components. Multimodal analgesic treatments especially postoperatively, are often based on opiods and require an intravenous catheter for drug application. This might impede early mobilisation and physiotherapy. Different composite pain scales and sensory testing devices exist to evaluate postoperative pain behaviour in dogs. At present, no data are available to clearly recommend one tool or technique after spinal surgery over others.\u003c/p\u003e\n\u003cp\u003eTherefore, the primary aim of this study was to evaluate if, subcutaneously applied methadone or transdermal fentanyl can offer sufficient postoperative analgesia in dogs after thoracolumbar neurosurgery without the necessity of keeping an intravenous access. A secondary aim was to evaluate which type of pain recognition tool would be suitable in this dogs in a clinical setting.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMethods\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn a prospective, randomised, clinical study client fifty client owned dogs were repeatable evaluated for 96h post spinal surgery. Treatments groups M received 0.4 mg/kg methadone subcutaneously two hours before start of surgery and following this every 6 hours. Treatment group F received topical applied 2.6 mg/ kg transdermal – fentanyl, two hours before start of the surgery. Dogs were assessed using the Glasgow composite measure pain scale – short form (CMPS-SF), the Colorado State University canine acute pain scale (CPS), a visual analogue scale and von Frey Monofilaments. Treatments groups were compared using the Wilcoxen rang sum test. Correlation between the three pain score was evaluated using the Spearman Rang correlation coefficient.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eResults\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAt no time point, any of the used methods could demonstrate a significant difference between analgesic requirements between groups M and F (p \u0026lt; 0.05). In both treatment groups pain scores of all three scales decreased over time. Results of the different pain scales correlated moderately to strongly. Utilising von Frey Filaments, results for skin sensitivity showed large individual variation, with a tendency towards reaction only at thicker filaments.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConclusion\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSubcutaneously methadone or transdermal fentanyl can provide adequate postoperative analgesia in dogs after spinal surgery without an intravenous catheter. The CMPS-SF and the CPS could reliably be used in this category of animal.\u003c/p\u003e","manuscriptTitle":"Subcutaneous methadone is not different than transdermal fentanyl for postoperative analgesia in dogs with thoracolumbar disc disease, using three different pain scales and von Frey Filaments, a prospective, randomised, blinded clinical study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-25 09:40:47","doi":"10.21203/rs.3.rs-6201354/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-13T19:50:40+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-03T12:46:17+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-29T13:58:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"110251400377904794323638790091945185453","date":"2025-04-28T13:01:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"15424550918876657491939573705702625622","date":"2025-04-26T14:16:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"334176147521554386352095461015404926319","date":"2025-04-26T07:42:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-19T21:13:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-19T20:53:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-03-18T15:00:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-18T13:33:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Veterinary Research","date":"2025-03-18T13:32:16+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-veterinary-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [BMC Veterinary Research](http://bmcvetres.biomedcentral.com/)","snPcode":"12917","submissionUrl":"https://submission.nature.com/new-submission/12917/3?","title":"BMC Veterinary Research","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8881aa58-633a-4fc6-a4e9-c3e8837cd528","owner":[],"postedDate":"March 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-06T16:04:10+00:00","versionOfRecord":{"articleIdentity":"rs-6201354","link":"https://doi.org/10.1186/s12917-025-04941-3","journal":{"identity":"bmc-veterinary-research","isVorOnly":false,"title":"BMC Veterinary Research"},"publishedOn":"2025-10-03 15:58:08","publishedOnDateReadable":"October 3rd, 2025"},"versionCreatedAt":"2025-03-25 09:40:47","video":"","vorDoi":"10.1186/s12917-025-04941-3","vorDoiUrl":"https://doi.org/10.1186/s12917-025-04941-3","workflowStages":[]},"version":"v1","identity":"rs-6201354","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6201354","identity":"rs-6201354","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}