Prior research shows that individuals insured by Medicaid who have chronic pain diagnoses are more likely than those who are privately insured to receive opioid pain medication, and those with co-morbid mental health and substance use disorders are more likely to receive opioid treatment for chronic pain than those without such diagnoses.Determining the causes of chronic pain in this population, as well as the relationships between chronic pain, comorbid conditions, and the receipt of opiates are important directions for future research. Chronic pain management is challenging due to the nature of the condition and the limited data on the efficacy of any treatment strategy. This challenge is especially true in a population with severe, chronic pain, poor access to longitudinal care, limitations in medications that can be used safely, and exposure to difficult environmental conditions. The high prevalence of chronic pain in people experiencing homelessness will require responses that address both pain and mental health problems that are adaptable to the needs of this growing population. Naturally occurring and iatrogenic hypercortisolism are common disorders in dogs, causing clinical signs that include polyuria and polydipsia , polyphagia, thin skin, excess panting, bilaterally symmetrical truncal hair loss, and muscle weakness. Muscle weakness,indoor cannabis grow system secondary to chronic glucocorticoid excess, likely contributes to the “pot belly” appearance and exercise intolerance noted frequently in dogs with HC.
Severe muscle stiffness is rare in dogs with HC and when present has been characterized by persistent bilateral muscle contraction of the thoracic legs, pelvic legs, or all 4 legs. The dogs reported to have concurrent HC and SMS have had typical clinical signs of HC but rather than muscle weakness they have non-painful SMS resulting in a bilateral extremely stiff and stilted gait. Even when lying down, affected dogs exhibit severe persistent extensor rigidity. The combination of SMS in dogs with HC, clinically, has been referred to as “Cushing’s myotonia.”Reported electromyography results from dogs with HC and SMS include “myotonic,” bizarre, high-frequency discharges.Muscle histopathology in dogs with typical HC and weakness includes Type II muscle fiber atrophy while those with concurrent HC and SMS have fiber size variation, focal necrosis, fiber splitting, subsarcolemmal aggregates, and fatty infiltration.Evidence of demyelination in some of these dogs on nerve conduction studies is consistent with a chronic neuropathy.To the authors knowledge, fewer than 20 dogs with HC and SMS have been described.In addition to treating HC, some of those dogs were administered medications to reduce or eliminate the SMS but no treatment resolved the SMS.The pathogenesis, treatment, short- and long-term prognosis of dogs with HC and SMS are unclear.The aim of the present study was to evaluate a larger number of dogs with concurrent HC and SMS to allow analysis of signalment, presentation, treatment, and outcome.In the interest of providing a geographically broad perspective, at least 1 veterinary colleague from Asia, North America, South America, The United Kingdom, and Europe was invited to submit to 1 author case information on dogs with concurrent HC and SMS.
In total, 14 colleagues from 10 institutions submitted data on dogs from their personal and institutions’ records.For inclusion, dogs must have had at least 3 of the following clinical signs of HC: PU/PD, polyphagia, hair loss, thin skin and excessive panting. Dogs must have had obvious abnormal muscle stiffness of the thoracic limbs, pelvic limbs, or all 4 limbs; no evidence of muscle weakness; and no evidence of any other cause for SMS . For inclusion, each dog with naturally occurring HC must have had at least 1 abnormal endocrine screening test result . Each dog with iatrogenic HC must have had a history of glucocorticoid administration and abnormally suppressed ACTHst and endogenous ACTH [eACTH] results.Discrimination of pituitary-dependent hypercortisolism from adrenaldependent hypercortisolism was determined using results of abdominal ultrasonography, LDDSt, and eACTH concentrations. Dogs were excluded if they had signs or laboratory abnormalities inconsistent with HC . Data submitted for each dog were to include signalment , history, clinical findings, complete blood counts , routine serum bio-chemistries, urinalyses, and endocrine test results at time of HC diagnosis, plus the time sequence of diagnosing HC and SMS. Abnormalities detected via diagnostic imaging were to be included. Presence of concurrent disorders must have been described. If performed, results of electrodiagnostic tests , muscle, and nerve biopsies were to be submitted.
Therapies employed for either HC or SMS and response to treatments were abstracted. “Progression” of SMS was defined as an inability to walk after being ambulatory at diagnosis or when stiffness was observed in additional limbs or masticatory muscles not involved when SMS was initially diagnosed. When available, cause of death was included.Collected data were managed with an electronic spreadsheet and analyzed using a commercial statistical data analysis software program . The Shapiro-Wilk test was used to assess the normality of continuous data. General and clinical characteristics of dogs with HC and concurrent SMS were summarized using mean and SD, median and range, or absolute and percentage frequencies, as appropriate. A Kaplan-Meier curve was performed to assess survival from the time that SMS was diagnosed. Data were censored if the animal was still alive or lost to follow-up at the end of the study period and survival times were reported as medians .Thirty-seven dogs with HC and concurrent SMS met the inclusion criteria; 6 from the Federal University of Rio Grande do Sul , 5 from the University of Bologna , 5 from the University of Parma , 5 from the University of California , 4 from the University of Buenos Aires , 3 from the Naya Especialidades of Sao Paulo , 3 from the Texas A&M University , 3 from the University of Pennsylvania , 2 from the University of Glasgow ,” and 1 from the Chungnam National University . The earliest date of concurrent HC and SMS diagnosis in a dog was 1984 and the most recent was 2021, with 14 males and 23 females in total. Breeds included 13 mixed-breed dogs, 10 Poodles, 4 Dachshunds, 2 Maltese, and 1 each Pembroke Welsh Corgi, Italian Greyhound, Jack Russel Terrier, Lhasa Apso, Italian Hound, Pinscher, Yorkshire Terrier, and Whippet. The median body weight was 7.7 kg and the mean age at the time of HC and SMS diagnosis was 10.8 years and 11.5 years , respectively.Clinical signs of HC included PU/PD , dermatologic abnormalities , polyphagia , abdominal enlargement , lethargy , and panting . Several dogs were described as weak at the time that HC was diagnosed, before they developed SMS. No dog had muscle weakness, and all were described as having abnormally “firm” muscles when SMS was diagnosed. CBCs,cannabis grow equipment serum biochemistries and urinalyses from each dog were consistent with HC. Serum creatine kinase activity results were available at diagnosis in 18 dogs; 13 were above the upper reference range . Of the 37 dogs, 19 had concurrent medical conditions , none of which were believed to alter the diagnosis of HC or SMS although phenobarbital is recognized to interfere with the diagnosis of HC in some dogs. Results of LDDSt, ACTHst, and UCCR were consistent with a diagnosis of HC in 22, 16, and 5 of 37 dogs, respectively. Test results from each dog were consistent with naturally occurring PDH; no dog had ADH or iatrogenic HC. Testing to discriminate PDH from ADH included abdominal ultrasonography and eACTH .
Pituitary magnetic resonance imaging and computed tomography scans were obtained after PDH had been diagnosed. Pituitary masses were seen in 4 dogs. Results of EMGs from 14 dogs exhibited complex repetitive discharges and occasional myotonic discharges, fibrillation potentials, and positive sharp waves . The epaxial and proximal appendicular muscles were more affected than the distal appendicular muscles. Seven dogs underwent NCS. Muscle and nerve biopsies were obtained from 7 dogs. Muscle biopsies demonstrated variation in muscle fiber size, subsarcolemmal and intermyofibrillar mitochondrial aggregates, moderate fibrosis in 5 out of 7 dogs . Two dogs had atrophy of type II muscle fibers, 1 of these 2 also had increased muscle fatty deposition. Nerve biopsies demonstrated hypomyelination or demyelination with occasional axonal degeneration in 5 out of 7 dogs . Abnormalities were not detected in the histology of 2 dogs. One dog died 8 days after being diagnosed with HC and SMS before any treatment had been given. Thirty-six dogs were treated for HC, 30 with trilostane ; 8 received the drug once daily and 22 q12. Eight dogs were treated with mitotane, including 2 dogs after treatment with trilostane did not resolve HC and 1 dog that was also administered melatonin. Clinical signs of HC improved dramatically or resolved in 28/36 treated dogs. Eight dogs, each treated with trilostane, showed no resolution of HC signs: 5 never responded despite increasing doses, 2 dogs transiently improved and then relapsed despite increasing doses; 1 dog died before completing the first month of treatment. Two dogs initially treated with trilostane without response had resolution of clinical signs after being switched to mitotane. In addition to treatment for HC, 19 of the 36 dogs were given medication for other medical conditions; 5 with ursodeoxycholic acid, 4 with levothyroxine, 3 with clopidogrel, 2 with insulin, 2 with ACE-inhibitors , 3 with gabapentin, 1 dog each with metronidazole, amlodipine, pregabalin, phenobarbital, and firocoxib. Twenty-three of the 37 dogs were diagnosed with SMS after the initial diagnosis of PDH had been established and treatment begun: 1 dog 1 month later, 14 dogs 2-12 months later, and 8 dogs >1 year later. Nineteen of these 23 dogs had a good response to treatment for HC, 3 failed to demonstrate a response, and 1 was euthanized before completing the first month of trilostane treatment. SMS was diagnosed before PDH in 11 dogs: in 2 dogs 2 months before diagnosis of HC, in 8 dogs 2-12 months before diagnosis of HC and in 1 dog more than 12 months before diagnosis of HC. Hypercortisolism and SMS were diagnosed at the same time in 3 dogs. When limb stiffness was initially identified, only the pelvic limbs of 22 dogs were involved, only the thoracic limbs of 6 dogs, and all 4 limbs in 9 dogs. No dog had 1 or 3 limbs involved and no dog had only unilateral involvement. Difficulty prehending, chewing, or swallowing was not reported in anydog at the time that SMS was diagnosed. No dog appeared in pain to the owner or veterinarian. Therapies directed at resolving or improving the SMS were administered to 19 dogs . Mild improvement was noted in 5 dogs treated with diazepam, mexiletine, physiotherapy, acupuncture and cannabis. Some improvement in SMS, after administration of trilostane was stopped because of iatrogenic hypocortisolism, was observed in 1 dog also being treated with physiotherapy and diazepam. Of 5 dogs that showed mild muscle improvement, 2 were being treated with trilostane once daily and 3 were being treated with trilostane q12. These 5 dogs then had no further change in SMS; 20 dogs never exhibited improvement or progression in SMS after the initial diagnosis; 11 dogs exhibited SMS progression. Two of 11 dogs with progressive SMS developed masticatory muscle involvement that caused difficulty chewing and swallowing. The dog treated with mitotane had also been managed with physiotherapy, acupuncture, and diazepam. The dog treated with trilostane had also been managed with physiotherapy, cyclobenzaprine, botulinum toxin, and diazepam. This dog was still alive at the time of writing and diazepam seemed to help with masticatory muscles relaxation. The other dog was euthanized because of SMS progression. In total, 14 dogs were euthanized, 7 because of persistent or progressive SMS, 1 because of persistent signs of HC, 6 were because of illnesses unrelated to HC, SMS, or its treatment. Three dogs died of other causes, 14 were alive at the time of writing, and 6 were lost to follow-up. Cause of death or euthanasia was not provided for 9 dogs. The median survival time from the diagnosis of SMS was 965 days .Breed, sex, age, clinical signs, CBCs, routine serum biochemistries, except for creatinine kinase activities results, and urinalyses at the time of HC diagnosis in the 37 dogs with HC and SMS in this study were similar to those described for dogs with naturally occurring HC but without muscle rigidity.As a group, the dogs with HC and SMS tended to be small, only 3 dogs weighed >15 kg and just 1 dog weighed >20 kg.