Introduction
Pain is a common clinical complication of cancer. Systematic reviews in human oncology have estimated that nearly two-thirds of patients with advanced or metastatic cancer suffer from pain1 and one-third of patients living with cancer experience inadequately treated pain.2 The incidence and characteristics of cancer pain in veterinary patients remain poorly understood,3,4 but given the similarities in clinical presentation and cancer biology across species, it is reasonable to presume that companion animals experience a similar frequency and degree of cancer pain.3 An owner survey-based study5 determined the prevalence of pain to be 75.2% in dogs with solid tumors. Cancer pain may arise secondary to direct tumor invasion of tissues, cancer treatment such as surgery and radiation, paraneoplastic syndromes, or preexisting concurrent disease.3 It can manifest as nociceptive pain originating from the tumor itself and/or secondary neuropathic pain, a pain syndrome caused by dysfunction of the somatosensory nervous system.6 In dogs with bone tumors, this pain has been characterized by peripheral and central sensitization with a deficient inhibitory system and may be refractory to most common palliative analgesic treatments.7
Cancer-related pain and chronic pain can have a profound impact on a patient’s quality of life. In order to effectively palliate cancer pain, multimodal analgesia is often needed, which involves the use of a combination of analgesic drugs to target different locations along the pain pathway.8 The approach to treatment of cancer pain has traditionally been stepwise and multimodal, involving a combination of anti-inflammatories, gabapentinoids, and opioids, prescribed according to the WHO 3-step analgesic ladder.9 Since many cancer patients receiving opioids still experience uncontrolled pain, the WHO ladder has been revised and recent advances have involved investigating nonconventional neuromolecular targets utilizing additional pharmacologic and nonpharmacologic treatments for pain, such as antidepressants, anticonvulsants, local nerve blocks, epidurals, patient-controlled analgesia pumps, and integrative therapies.10,11
N-methyl-D-aspartate (NMDA) receptors play a key role in central sensitization. Low (ie, subanesthetic) doses of ketamine, an NMDA-receptor antagonist, have been shown to decrease central sensitization and subsequent hyperalgesia in the range of 0.1- to 0.5-mg/kg bolus followed by 1- to 2-µg/kg/min constant rate infusion doses,12 making it an attractive therapy for cancer pain where central sensitization is established. It is often administered as an IV continuous rate infusion, although other administration routes and bolus administration are utilized. Ketamine acts on a variety of additional receptors including opioid, L-type calcium channels, muscarinic, and monoaminergic.13 Given the opioid epidemic and subsequent need to reduce opioid usage to avoid diversion within the profession and, more so, given the inflammatory response, gastrointestinal side effects, and even metastatic potential of opioids,14,15 ketamine has taken an important lead in reducing misuse, opioid-induced hyperalgesia/inflammation, and nausea within the confines of chronic pain therapy.
Lidocaine is an amide local anesthetic that can be used as a systemic analgesic through IV constant rate infusions. Multiple mechanisms of action appear to produce analgesia, including voltage-gated ion channel inhibition, reduction of inflammatory cytokines, and NMDA-receptor antagonism at higher doses.3,4,16 In dogs and cats experiencing acute postoperative pain from ovariohysterectomy, infusions of ketamine and lidocaine, with dexmedetomidine and maropitant, respectively, have been shown to reduce the need for rescue analgesia and lower pain scores without adverse effects.17,18 Additionally, both systemic ketamine and lidocaine, alone and in combination, are safely used together with opioids for the treatment of refractory neuropathic pain, including cancer pain, in humans.13,19–25
The use and efficacy of IV infusions of ketamine and lidocaine as adjunctive treatment for refractory cancer pain in veterinary patients are unreported. The authors hypothesized that ketamine-lidocaine (KL) infusions would be an effective adjunctive analgesic for dogs and cats with cancer. The primary objectives of this retrospective case series were to evaluate adverse events and impact on owner-perceived pain level and clinical signs (clinical benefit) following outpatient infusions of ketamine and lidocaine for palliation of cancer pain in dogs and cats.
Methods
Case selection
Electronic medical records were searched to identify dogs and cats that received palliative KL infusions for cancer pain at Cornell University Hospital for Animals from 2008 to 2023. Dogs or cats with a cancer diagnosis that received at least 1 KL infusion through the Oncology Service were included.
Ketamine-lidocaine infusion protocol
Animals were prescribed ketamine (0.9 mg/kg) and lidocaine (18 mg/kg). The drugs were diluted in a single saline bag (250 mL [cats or dogs < 15 kg] or 500 mL [dogs ≥ 15 kg] of 0.9% saline) and administered on a fluid pump (Flo-Gard 6200 Volumetric Infusion Pump; Baxter International Inc) at a rate of 2.5 mL/kg/h. The target infusion rates were 0.15 mg/kg/h of ketamine and 3 mg/kg/h of lidocaine. A loading dose was not administered. The infusion was stopped after 4 to 6 hours, duration and volume infused were recorded in the medical record, and total doses administered were calculated, along with controlled drug waste. The infusions were repeated every 2 to 4 weeks, as dictated by the duration of benefit appreciated and oncologic recheck schedule. For analysis, actual administered dosages were divided into ultralow-dose and low-dose groups, with a cutoff for ultralow dose defined as total ketamine dose < 0.5 mg/kg and/or ketamine infusion rate < 2 µg/kg/min and lidocaine infusion rate < 25 µg/kg/min, based on supporting literature.26–28
Response assessment and toxicity grading
The recommended follow-up schedule included a recheck examination 2 weeks after the first KL infusion and every 2 to 4 weeks thereafter for continued palliative care. Clinical signs (improvement in appetite, ability to eat, activity level, pain scores, and/or lameness) were recorded from history questionnaires (Table 1) filled out by owners upon arrival to the hospital and physical examination findings in the medical record. Clinical benefit was defined as an improvement in at least one of the evaluated clinical signs and was considered clinically relevant if it lasted longer than 2 weeks and/or until recheck. Addition, discontinuation, or percent change in dose of concomitant oral analgesics and the dates of these adjustments with respect to initial KL infusion were recorded. Medications that were discontinued > 2 weeks prior to KL infusion were excluded.
Owner-reported history questionnaire scoring.
| Clinical sign and score | No pain | 1 | 2 | 3 | 4 | U |
|---|---|---|---|---|---|---|
| Appetite | Anorexia | Poor | Decreased | Normal | — | — |
| Difficulty eating | No | Yes | — | — | — | — |
| Activity level | Lethargic/unwilling to move | Severely decreased | Moderately decreased | Mildly decreased | Normal | — |
| Lameness | No | Yes | — | — | — | — |
| Pain level | Not pain | Mild pain | Moderate pain | Severe pain | Disabling pain | Unsure |
U = Owner unsure.
Hematocrit, hemoglobin, ALT, total bilirubin, BUN, and creatinine were recorded prior to first infusion and at the first recheck appointment. Toxicities were graded according to Veterinary Cooperative Oncology Group Common Terminology Criteria for Adverse Events.29 Animals were assigned a grade of 0 if no adverse event occurred. Any contemporaneous gastrointestinal, cardiac, or neurologic changes were recorded as potential toxicities, as they could not definitively be distinguished from disease progression retrospectively.
Follow-up duration, disease progression, and cause of death were recorded. Disease progression was defined as recurrence or worsening of clinical signs, objective tumor progression on physical examination or imaging, metastasis, or death. Site of progression (local or systemic/distant metastasis) was recorded. Progression-free survival was defined from the date of the first KL infusion until progression or death. Overall survival was defined from diagnosis until death.
Statistical analysis
Descriptive statistics were reported with mean and SD for normally distributed data or median and IQR or range for nonnormally distributed data, as determined by a Shapiro-Wilk test. To compare whether the infusion protocol between treated dogs and cats and patients > or < 15 kg differed, the Kruskal-Wallis test was used for continuous variables and Fisher exact tests were used for categorical variables. Progression-free and overall survival were modeled with a Kaplan-Meier curve and 95% CI. Variables were evaluated for their impact on survival with a Cox proportional hazards model. To assess the impact of continuous variables on clinical benefit, 1-way ANOVA was used. To assess the impact of categorical variables on clinical benefit, Pearson χ2 and likelihood ratios were used. Statistical analysis was performed with JMP Pro (version 16; SAS Institute Inc).
Results
Case selection and patient characteristics
A total of 105 dogs and 9 cats (114 animals) treated with palliative KL infusions for cancer pain were included. There were 31 mixed-breed dogs and 74 purebred dogs. The most represented breeds were Golden Retriever (18 of 74 [24%]), Labrador Retriever (9 of 74 [12%]), Rottweiler (6 of 74 [8%]), and Saint Bernard (3 of 74 [4%]). All cats were domestic shorthairs. Additional patient demographics, tumor types, and tumor anatomic locations were recorded in Table 2. The most common tumor location in dogs was appendicular bone (45 of 105 [43%]). In cats, oral (4 of 9 [44%]) and sinonasal (3 of 9 [33%]) tumors were most common. The most common tumor types treated were osteosarcoma in dogs (50 of 105 [48%]) and oral squamous cell carcinoma in cats (4 of 9 [44%]). Thirty-four animals had regional and/or distant metastasis (34 of 108 [31%]), 74 did not (74 of 108 [68%]), and 6 had not undergone staging (6 of 114 [5%]).
Patient demographics, tumor types, and tumor locations treated.
| Dogs (n = 105) | Cats (n = 9) | |
|---|---|---|
| Median (range) age (y) | 9 (3–16) | 13 (0.7–16) |
| Median (range) weight (kg) | 32.1 (5–68.7) | 3.9 (2.5–5.8) |
| Sex (IF/SF; IM/CM) | 3/46; 49/7 | 1/3; 0/5 |
| Tumor location | ||
| Bone | 83 | 7 |
| Digit | 3 | 0 |
| Limb | 45 | 0 |
| Nasal | 3 | 3 |
| Multiple sites | 2 | 0 |
| Oral | 13 | 4 |
| Pelvis | 4 | 0 |
| Rib | 2 | 0 |
| Skull | 1 | 0 |
| Trachea/larynx | 1 | 0 |
| Vertebra | 9 | 0 |
| Soft tissue | 22 | 2 |
| Nerve | 3 | 0 |
| Pleural | 1 | 0 |
| Subcutaneous/intramuscular | 15 | 2 |
| Visceral | 3 | 0 |
| Tumor type | ||
| Sarcoma | 75 | 3 |
| Chondrosarcoma | 2 | 0 |
| FROMS | 0 | 1 |
| Fibrosarcoma | 2 | 1 |
| Hemangiosarcoma | 3 | 0 |
| Lymphangiosarcoma | 1 | 0 |
| Osteosarcoma | 50 | 0 |
| Osteolytic lesion, not sampled | 6 | 0 |
| Peripheral nerve sheath tumor | 2 | 0 |
| Sarcoid | 0 | 1 |
| Soft tissue sarcoma | 7 | 0 |
| Not specified | 2 | 0 |
| Carcinoma | 18 | 6 |
| Adenocarcinoma | 3 | 1 |
| AGASACA | 2 | 0 |
| Ameloblastic | 1 | 0 |
| Basosquamous | 1 | 0 |
| Mammary, inflammatory | 1 | 0 |
| MCUP | 1 | 0 |
| Squamous cell | 5 | 4 |
| Urothelial | 1 | 0 |
| Not specified | 3 | 1 |
| Round cell | 12 | 0 |
| Histiocytic sarcoma, periarticular | 5 | 0 |
| Lymphoma | 1 | 0 |
| Plasma cell tumor | 2 | 0 |
| Mast cell tumor | 4 | 0 |
AGASACA = Apocrine gland anal sac adenocarcinoma. CM = Castrated male. FROMS = Feline restrictive orbital myofibroblastic sarcoma. IF = Intact female. IM = Intact male. MCUP = Metastatic carcinoma of unknown primary. SF = Spayed female.
Most animals (60 of 114 [53%]) had undergone treatment with at least 1 previous cancer therapy. This included chemotherapy (n = 25), radiation therapy (38), and surgery (26), alone (36) or in sequence or combination (24). Eight animals had undergone both radiation and chemotherapy, 5 had undergone both surgery and chemotherapy, 6 had undergone both surgery and radiation, and 5 had undergone a combination of all 3 treatments. There were 14 animals that received chemotherapy and 41 that received palliative radiation therapy concurrently with KL infusions.
All animals received concomitant analgesic therapy, which included at least 1 oral analgesic medication in 114 of 114 animals (100%). Additional analgesic treatment included nerve blocks in 21 of 114 (18%), acupuncture and/or traditional Chinese medicine in 16 of 114 (14%), bisphosphonate infusions in 51 of 114 (45%), intermittent fentanyl patches in 3 of 114 (3%), and topical lidocaine cream in 1 of 114 (1%).
Before administration of KL infusions, the median number of concomitant oral analgesic medications animals were receiving was 3 (range, 1 to 4 medications). Oral analgesic medications included NSAIDs in 80 of 114 (70%), steroids in 53 (46%), gabapentinoids in 105 (92%), opioids in 77 (68%), amantadine in 20 (18%), and acetaminophen in 1 (< 1%). After starting KL infusions, the number of concomitant medications required to control pain decreased in 13 of 114 animals (12%), increased in 7 animals (6%), and did not change in the remaining 93 animals (82%). Dose adjustments to concomitant analgesic drugs relative to first KL infusion were recorded in Table 3.
Concomitant analgesic drugs and dose adjustments relative to first ketamine-lidocaine infusion.
| Drug class | No. (%) of animals | Drug (n) | T of drug start (d relative to first infusion) Median (IQR) | Dose change | Discontinuation | ||||
|---|---|---|---|---|---|---|---|---|---|
| No. (%) of animals | % dose change Median (IQR) | T of dose decrease (d) Median (IQR) | T of dose increase (d) Median (IQR) | No. (%) of animals | T (d) | ||||
| NSAIDs | 80 (70) | Carprofen (42) | –37 (–95 to –9) | 6 (7.5) | –35 (–48 to 49) | –0.5 (–6.3 to 84) | 15.5 (–2 to 33) | 24 (30) | 2.5 (–27 to 21) |
| Meloxicam (18) | |||||||||
| Firocoxib (8) | |||||||||
| Deracoxib (7) | |||||||||
| Galliprant (4) | |||||||||
| Piroxicam (1) | |||||||||
| Steroids | 53 (46) | Prednis(ol)one (49) | –2 (–15 to 3) | 17 (32) | –31 (–50 to 93) | 13.5 (5.2 to 65.9) | 1 (0 to 58) | 13 (24.5) | –1 (–9 to 34) |
| Dexamethasone (3) | |||||||||
| Methylprednisolone acetate (1) | |||||||||
| Gabapentinoids | 105 (92) | Pregabalin (48) | –11 (–41 to 0) | 27 (26) | 50 (–25 to 89) | 0 (–85 to 26) | 15 (–1.8 to 52.5) | 5 (5) | 35 (–7.5 to 73) |
| Gabapentin (41) | |||||||||
| Alternated (16) | |||||||||
| Opioids | 77 (68) | Oxycodone (41) | –7 (–29 to 0) | 7 (9) | 36 (22 to 93) | 13 (1 dog) | 13.5 (–2 to 89) | 10 (13) | 22 (–2.5 to 40) |
| Tramadol (29) | |||||||||
| Buprenorphine (5) | |||||||||
| Codeine (1) | |||||||||
| Hydrocodone (1) | |||||||||
| Amantadine | 20 (18) | Amantadine (20) | 0 (–3 to 26) | — | — | — | 2 (10) | 44.5 (0 to 89) | |
T = Timing.
Ketamine-lidocaine infusion protocol
Complete KL dosing and administration information was available for 81 dogs and 9 cats (90 of 114 [79%]) and recorded in Table 4. The exact number of KL infusions received was not known in 6 animals, as KL infusions were continued at their primary care veterinarians and they were lost to follow-up; this left 108 animals for which the number of KL infusions was known. The median total doses and administration rates of both ketamine and lidocaine were significantly lower in animals weighing < 15 kg and cats compared to dogs.
Ketamine-lidocaine infusion parameters and dosages.
| Infusion parameter | Median | Range | P value between dogs and cats | P value between animals < or > 15 kg |
|---|---|---|---|---|
| Length of infusion (h) | 5 | 4–6 | .8233 | — |
| IV fluid rate (mL/kg/h) | 2.47 | 2.3–2.53 | .0714 | .6479 |
| Total fluid dose (mL/kg) | 12.4 | 9.8–14.5 | .2384 | — |
| Total ketamine dose (mg/kg) | 0.69 | 0.39–0.89 | .0222 | < .0001 |
| Total lidocaine dose (mg/kg) | 14.2 | 8.46–18.0 | .0150 | < .0001 |
| Ketamine administration rate (mg/kg/h) | 0.14 | 0.09–0.17 | .0161 | < .0001 |
| Lidocaine administration rate (mg/kg/h) | 2.8 | 1.6–3.4 | .0117 | < .0001 |
Of the animals for which the number of infusions was recorded, 51 of 108 (47%) received only 1 KL infusion. Fifty-three percent (57 of 108) received more than 1 KL infusion, with a median of 2 infusions performed (IQR, 2 to 5; range, 2 to 49 infusions). Forty-two (74%) pets received 2 to 5 KL infusions, 10 of 108 (17.5%) received 6 to 10 infusions, 3 of 108 (5%) received 11 to 20 infusions, and 2 of 108 (3.5%) received > 20 infusions. Of the 5 animals receiving > 10 infusions, 1 was a cat (20 infusions) and 4 were dogs (11, 13, 26, and 49 infusions). The total number of KL infusions received did not vary between dogs and cats (P = .9953).
The median interval between KL infusions was 27.5 days (IQR, 18.3 to 34.5). This did not vary between dogs and cats (P = .9007). The median duration of follow-up was 63.5 days (IQR, 25 to 172), with 82% (94 of 114) and 73% (83 of 114) having a follow-up duration > 14 days and > 28 days, respectively. Median time from diagnosis to start of KL infusion was 35 days (range, 0 to 1,957 days). Seventeen animals (14.9%) received their first KL infusion within 3 days of their cancer diagnosis.
Response assessment
The primary reason for prescribing the KL infusion was refractory pain associated with osteolysis (n = 93 [81%]); subcutaneous and intramuscular tumor invasion (10 [9%]); radiation therapy side effects including desquamation, mucositis, and osteonecrosis (5 [4%]); visceral pain (4 [4%]); and neuropathic pain (2 [2%]). Clinical benefit assessment was available in 92 animals (86 dogs and 6 cats [81% overall; 82% of dogs and 67% of cats]), with a median of 3 assessable clinical signs recorded. The overall clinical benefit rate was 76% (70 of 92 had improvement in at least 1 clinical sign). Median weight change from KL infusion to first recheck was –1.35% (IQR, –5.56% to 1.65%), but 34 of 81 animals (42%) gained weight and 8 (10%) had an increase of 5% of body weight or greater. Changes in scores for individual clinical signs are shown in Figure 1. Seventy-five percent (58 of 77) of animals experienced improvement in appetite, 56% (5 of 9) had reduced difficulty eating, 89% (56 of 63) experienced improvement in activity level, 65% (35 of 54) had improved lameness, and 65% (33 of 51) experienced decreased owner-perceived pain level. The only 2 variables found to significantly impact clinical benefit were (1) the number of KL infusions administered (P = .0154), with an increased number of infusions positively associated with response, and (2) whether the animal was < 15 kg (P = .0078), with smaller animals less likely to respond (71% of patients < 15 kg had a clinical response compared to 91% of animals ≥ 15 kg [P = .0441]).
Improvement in clinical sign scores. A change of 0 equated to no change, whereas a positive score corresponded to improvement and negative score to worsening of the clinical sign. Median improvement in appetite (unfilled box) was 0 (IQR, –0.5 to 1), with a mean of –0.14 (SD, 1.37). Median improvement in activity level (light-gray box) was 0 (IQR, 0 to 1), with a mean of 0.42 (SD, 1.28). Median improvement in difficulty eating (dark-gray box) was 1 (IQR, 0 to 1), with a mean of 0.56 (SD, 0.53). Median improvement in lameness (gray checkered box) was 1 (IQR, 0 to 1), with a mean of 0.65 (SD, 0.48). Median improvement in pain levels (striped box) was 1 (IQR, 0 to 1), with a mean of 0.88 (SD, 1.16). Keto-lido = Ketamine lidocaine.
Citation: Journal of the American Veterinary Medical Association 2025; 10.2460/javma.24.09.0595
Species (P = .2515); tumor location (bone vs other; P = .3820); concomitant bisphosphonates (P = .1396); concomitant oral analgesics such as NSAIDs (P = .8864), steroids (P = .9601), gabapentinoids (P = .3318), opioids (P = .3842), and amantadine (P = .0882); saline volume (P = .1218); concurrent cancer therapy (P = .2585); type of concurrent therapy (either chemotherapy [P = .6758] or radiation therapy [P = .0686]); metastasis (P = .7636); and source of pain/reason for infusion (P = .1177) did not significantly impact clinical response. The likelihood of clinical response was improved with a ketamine infusion rate ≥ 2 µg/kg/min (P = .0374), total ketamine dose of ≥ 0.5 mg/kg (P = .0343), and lidocaine infusion rate ≥ 25 µg/kg/min (P = .0051), compared to ultralow doses. Animals that were < 15 kg were significantly more likely to receive ultralow doses of ketamine (P < .0001) and lidocaine (P < .0001).
Median overall survival (MST) from diagnosis was 135 days (95% CI, 107 to 175) and did not vary between dogs and cats (P = .7000). Progression-free survival from the first KL infusion was 60 days (95% CI, 44 to 94). This did not vary between dogs (MST, 61 days; 95% CI, 43 to 96) and cats (MST, 53 days; 95% CI, 4 to 228) (P = .7257). The number of KL infusions received was positively associated with longer progression-free survival (P = .0005).
Toxicity
Ninety-two animals were rechecked after KL infusion. Of these, 9 were reassessed by phone and 83 were reevaluated in person. Toxicity assessment was not performed in 22 animals, as 18 animals were lost to follow-up, 3 animals were euthanized, and 1 animal died before scheduled recheck. Median duration from the first KL infusion to recheck was 14 days (range, 1 to 46 days). Recheck blood work was available for 70 of 92 animals (76%) and collected at a median of 21 days (range, 1 to 105 days) after KL infusion. Adverse events were summarized for dog and cats in Table 5, with grade 1 anemia most common in both species.
Adverse events from ketamine-lidocaine infusions in dogs and cats.
| Adverse event | Median (range) | n (%) | |||||
|---|---|---|---|---|---|---|---|
| Baseline | First recheck | Grade 0 | Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
| In dogs (n) | |||||||
| Anemia/Hct (60) | 44% (13.6%–60%) | 43% (18%–56%) | 34 (57) | 23 (38) | 2 (3) | 1 (2) | N/A |
| ALT (48) | 51.5 U/L (13–1,686 U/L) | 58 U/L (15–2,240 U/L) | 32 (67) | 5 (9) | 10 (18.5) | N/A | 1 (2) |
| Total bilirubin (46) | 0.1 mg/dL (0–0.5 mg/dL) | 0.1 mg/dL (0–6.4 mg/dL) | 43 (94) | N/A | 2 (4) | N/A | 1 (2) |
| BUN (51) | 16 mg/dL (5–55 mg/dL) | 17 mg/dL (8–64 mg/dL) | 47 (92) | 2 (4) | 1 (2) | 1 (2) | N/A |
| Creatinine (51) | 0.85 mg/dL (0.4–2.1 mg/dL) | 0.9 mg/dL (0.5–2.2 mg/dL) | 47 (92) | 4 (8) | N/A | N/A | N/A |
| In cats (n) | |||||||
| Anemia/Hct (6) | 34% (24%–36%) | 34.5% (29%–48%) | 2 (33) | 4 (67) | N/A | N/A | N/A |
| ALT (6) | 32 U/L (25–40 U/L) | 31.5 U/L (20–109 U/L) | 5 (83) | 1 (17) | N/A | N/A | N/A |
| Total bilirubin (6) | 0 mg/dL (0–0.1 mg/dL) | 0 mg/dL (0–0 mg/dL) | 6 (100) | N/A | N/A | N/A | N/A |
| BUN (6) | 19 mg/dL (17–50 mg/dL) | 19 mg/dL (19–48 mg/dL) | 6 (100) | N/A | N/A | N/A | N/A |
| Creatinine (6) | 1.1 mg/dL (0.5–1.5 mg/dL) | 1.1 mg/dL (1.0–2.1 mg/dL) | 5 (83) | 1 (17) | N/A | N/A | N/A |
Possible toxicities aside from hematologic and biochemical changes included 1 dog diagnosed with first-degree atrioventricular block and sinus bradycardia under general anesthesia for radiation therapy 1 day after first KL infusion, which resolved following the anesthetic event. One additional dog had acute hemorrhage and possible disseminated intravascular coagulation 1 day following their first infusion, suspected to be secondary to cancer progression. No neurologic toxicities were documented.
In 2 dogs (2%), vomiting occurred during the KL infusion, which did not occur during subsequent infusions when premedicated with antinausea medication (maropitant citrate and/or ondansetron). Hypersalivation and lip licking without vomiting was also noted in one of these dogs when disconnected from the infusion, which improved with the addition of metoclopramide and glycopyrrolate before subsequent infusions. One animal had dull mentation after an unintentional rate increase (4 times the prescribed administration rate for an unknown time interval), but mentation returned to normal after the rate was decreased. Sedation or dysphoria related to the infusion was not recorded in any other animal. There were no toxicities noted during feline infusions.
Discussion
This retrospective case series reported the use of IV KL infusions for adjunctive management of cancer pain in dogs and cats. There was a high rate of clinical benefit with KL infusions (76%; as determined by retrospective evaluation of owner-reported clinical signs, quality of life, and pain) in both cats and dogs with a variety of different tumor types and locations, showcasing its versatility. Ketamine-lidocaine infusions can be administered on an outpatient basis, with a median duration of 5-hour infusions in this study, making them convenient for veterinarians and pet owners and useful in the palliative care setting as an adjunctive treatment for refractory cancer pain in both a general practice or referral setting. Although IV ketamine infusions in human patients can result in weeks to months of pain relief, this is generally true for higher total infused doses and prolonged infusion durations, although the rate of infusion does not appear to be a factor.30 The authors initially chose the 4- to 5-hour duration based on lack of side effects seen in prolonged surgeries with similar infusion rates. Additionally, 17% of included animals received their first KL infusion in an emergency inpatient setting. Management of cancer pain often requires multimodal analgesia, and KL infusions should be considered as a safe and clinically beneficial additional option to use in combination with anticancer therapy, oral analgesics, topical analgesics, and interventional therapies.
The median survival time of 135 days reflected the patient selection of animals with advanced and metastatic disease treated palliatively. The median survival from first KL infusion was 60 days, which is consistent with the prognosis for palliative treatment of the 2 most represented cancers herein, canine osteosarcoma31 and feline oral squamous cell carcinoma,32 as well as the authors’ opinion of anticipated prognosis for dogs and cats with uncontrolled pain receiving palliative care (1 to 3 months). The high rate of palliation seen was encouraging. Given the subjective owner assessment and retrospective nature of this evaluation, a major limitation of this study was the caregiver biases in these evaluations that likely overestimated improvement, which may also be reflected in the increased frequency of improvement in more subjective categories such as appetite and activity level. A more rigorous prospective evaluation with objective measures of pain, perhaps specific for each type of cancer and/or including cancer-related quality of life, is needed to more accurately assess clinical benefit.
Chronic pain from cancer in veterinary patients may be difficult to assess, as well as difficult to recognize, as signs may be subtle and vary by individual. Signs may include lessened appetite, sleep issues, gastrointestinal issues, withdrawn demeanor, decreased playing and socialization, stiff gait, lameness or trouble walking, reluctance to perform activities such as jumping, and reduced activity levels.33,34 Given that cancer and its treatment can cause both acute and chronic pain, animals in this study were likely experiencing mixed types of pain from a variety of causes. Most tools for assessing pain in veterinary patients were developed and validated in well-defined research populations, and their performance may be impacted when applied to mixed populations with comorbidities and uncontrolled environments.34 Assessing pain and quality-of-life measures from retrospective data was a major limitation of this study. An unvalidated but standardized history questionnaire was used at each visit as part of routine clinical practice, but retrospective interpretation of owner responses was still required. Given concern for caregiver placebo effect impacting both owner and veterinary assessments of pain in dogs with osteoarthritis,35 subjective reports were also likely an inadequate way of assessing an animal’s cancer pain and response to therapy and impacted the data reported herein.
The factors contributing to chronic cancer pain in animals are multifactorial and unique to the individual, adding to the challenge of effective cancer pain management. In this patient population, the addition of a gabapentinoid, steroid, NSAID, or opioid at a median negative number of days prior to first KL infusion reflected attempts at multimodal analgesia; receiving KL in addition to these concomitant medications supported that pain was still present and considered suboptimally controlled. In the majority of animals, a lack of dose increases in concomitant analgesics following a single KL infusion may be supportive of controlled pain in the time period between their KL infusion and recheck appointment. While discontinuation of an opioid, gabapentinoid, or amantadine after their first KL infusion occurred in only a minority of animals, it suggested a clinical benefit in these patients. However, it is not standard at our institution to challenge animals and decrease dosage or discontinue analgesic medications unless contraindicated or not well tolerated. Retrospective assessment of owner management of patient pain at home and administration of medications by the owner on an “as-needed basis” further limited assessment. The potential sparing effects of KL infusions on concomitant analgesia medications are not well understood currently.
The clinical protocol for KL infusions during the years this retrospective study was performed involved following a worksheet to determine how much ketamine and lidocaine to add to an IV saline fluid bag to achieve targeted doses for a 6-hour infusion. This technique was chosen due to ease of administration and level of care required compared to administering separate infusions. However, this resulted in increased controlled drug (ketamine) waste for smaller animals that received a smaller fraction of the fluid bag over the standard 4- to 6-hour period given their lower fluid rate proportional to body size, as well as clinically relevant underdosing. Animals < 15 kg were less likely to have a clinical response to KL infusions (P = .0078) and receive ultralow doses. In order to overcome this and ensure smaller animals receive the doses associated with an improved clinical response (ketamine infusion rate ≥ 2 µg/kg/min [P = .0374], total ketamine dose of ≥ 0.5 mg/kg [P = .0343], and lidocaine infusion rate ≥ 25 µg/kg/min [P = .0051]), the authors’ recommendation from the current data is to administer KL infusions in smaller animals as separate infusions, or dilute in a smaller volume (eg, 100-mL saline bag or syringe of total volume to be infused), and ensure that these target dosages are met in all animals.
Although minimal toxicity was noted with KL infusions in this population and it’s expected that these events, such as grade 1 anemia, were related to the patient’s disease and not intervention, adverse events may have been missed, particularly if not recorded in the medical record during the infusion or immediately after or if not captured on the blood work, given the nonstandardized and variable timing of rechecks. It is difficult to attribute adverse events retrospectively, particularly in patients with comorbidities. The authors took the inclusive approach of assuming all adverse events could be related to KL, likely overreporting. For example, 3 dogs that experienced elevated ALT after their first KL infusion had existing vacuolar hepatopathy or were receiving concurrent chemotherapy or steroids that likely contributed. Conversely, it has been previously reported that anesthetized cats administered lidocaine infusions have demonstrated increased cardiac and neurologic side effects compared to dogs.36 However, more recent research has demonstrated not only efficacy analgesically for both lidocaine and ketamine but also safety and opioid sparing as well.17-18 Feline cardiovascular and neurologic toxicities may not have been appreciated in this population given the administration method and resultant underdosing in animals < 15 kg. Additionally, biochemical changes were only assessed after the first KL infusion, although no toxicities with subsequent infusions were reported in the medical records. This was similarly true for how KL infusions impacted dosages of concomitant analgesic medications, where the impact of subsequent infusions was not distinctly assessed.
This retrospective study illustrated that KL infusions are well tolerated and safe, appear to provide clinical benefit for dogs and cats with cancer, and should be considered as an adjunctive analgesic therapy. Future studies will focus on prospective, randomized studies using ketamine and lidocaine in veterinary cancer patients with objective assessments of pain at specific dosages and routes of administration.
Acknowledgments
None reported.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.
Funding
The authors have nothing to disclose.
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