Each year, thousands of pet owners listen as their veterinarian informs them that their dog has a knee injury and may benefit from surgery. While medical management, such as cage rest and pain medications can help, surgery is the treatment of choice for stabilizing the knee or stifle joint.
The goal of surgery is not to repair the cranial cruciate ligament (CCL) itself – due to biological and mechanical influences, the ligament has no ability to heal once tearing begins regardless of the degree of severity. In a healthy dog, the CCL acts similarly to a human’s anterior cruciate ligament (ACL) by controlling motion of the femur relative to the tibia while the dog is walking. When the ligament is damaged, there is excess movement as the femur shifts slightly backwards when the dog puts weight on the knee. However, unlike in human ACL surgery, due to the degeneration of the cranial cruciate ligament, graft-based techniques are less reliable. There are several techniques that can be categorized into two groups based on different surgical concepts:
Osteotomy-based techniques involve cutting into the bone to alter how the muscles and bones move relative to each other, thereby altering the biomechanics of the knee. Tibial Tuberosity Advancement (TTA) and Tibial Plateau Leveling Osteotomy (TPLO) are common examples of this.
Suture-based techniques attempt to mimic the action of the torn ligament. The most commonly performed technique is called extra-capsular suture stabilization, which utilizes suture material that is placed just on the outside of the knee joint under the skin.
Each week, Bert Shelley, DVM, MS DACVS of Bradford Park Veterinary Hospital in Springfield, Missouri sees local referrals to perform several cranial cruciate ligament surgeries using the external capsular repair technique. His goal with the surgery is to “mimic” the function of the cranial crucial ligament with a suture placed in similar orientation to the original ligament. The long-term goal is to facilitate the formation of organized scar tissue around the joint that will provide additional stability.
Transforming Pain Control
The protocol for providing pain control to Dr. Shelley’s knee surgery patients is straightforward – a multi-modal approach using several types of pain control therapeutics that aims to allows the dog to return to normal function.
Dr. Shelley emphasizes that to him, a multi-modal approach is key because unmanaged, acute pain can lead to chronic, maladaptive pain, which is very difficult to manage.
“With a long-acting, local anesthetic, I would still use a multi-modal approach, but it would have the added benefit of getting a dog mobile quicker and providing them more comfort so they’re less restless the first few days,” notes Dr. Shelley.
In his experience as a surgeon on studies evaluating the safety and efficacy of NOCITA® (bupivacaine liposome injectable solution; see important safety information), he noticed a difference.
“Being a surgeon, I didn’t do the direct follow-up during the study, but I noticed that dogs handed off to the pain team seemed to be more comfortable from the beginning,” states Dr. Shelley.
“I think Nocita will be really beneficial for treating acute pain post-surgery within the first few days and using it during surgery means it may prevent pain receptors from being over stimulated. Once the pain receptors are stimulated by pain, it is difficult to get enough drugs into the body to stop the pain. I believe Nocita has the potential to be a real added benefit for surgeons.”
He also acknowledges that it is important to him that not only should a new option work, but it must be safe.
“The biggest thing is having a well-tolerated pain relief option. It’s something you worry less about talking to owners,” notes Dr. Shelley. “With Nocita, you’re not upping the opioid load and for pet owners, sometimes it’s hard to know when pets are in pain because they don’t show the same pain signs as people do. This gives the veterinarian peace of mind knowing pain is being controlled.”
How does NOCITA Work?
NOCITA is a long-acting local anesthetic administered as a single dose by tissue infiltration injection during closure of cranial cruciate ligament surgery in dogs. The therapeutic lasts up to 72 hours post-surgery by extending the release of bupivacaine over time from multivesicular liposomes deposited in the tissue. The multivesicular liposomes are composed of hundreds to thousands of chambers per particle, encapsulating aqueous bupivacaine.
Liposomes are microscopic structures made of nonconcentric lipid bilayers resembling a “honeycomb-like” matrix and are designed to allow bupivacaine to gradually release from vesicles over a period of up to 72 hours. The bupivacaine prevents propagation of nerve action potentials and transmission of pain signals.
The extended duration of action assists in preventing analgesia gaps in the first 72 hours post-surgery and provides a bridge between in-clinic pain control and at-home pain control after the patient is discharged.
The safety and efficacy of NOCITA has been studied in a multi-center, placebo-controlled, randomized and masked field study of 182 client-owned dogs undergoing cranial cruciate ligament stabilization surgery. Results showed NOCITA met efficacy success criteria of no rescue analgesia required as assessed by trained observers using the Glasgow Composite Measure Pain Scale-Short Form. The primary endpoint for effectiveness was evaluated in the first 24 hours and showed NOCITA provided statistically significant (p=0.0322) success rates (68.8 percent) compared to placebo (36.5 percent). The secondary endpoint confirmed NOCITA demonstrated statistically significant success rates for dogs compared to placebo for the 24-48 hour interval (64.3 percent to 34.6 percent respectively; p=0.0402) and for the 48-73 hour interval (61.6 percent to 32.7 percent respectively; p=0.0432), supporting effective use of NOCITA for up to 72 hours of analgesia. Results also showed NOCITA was well-tolerated and adverse reactions, such as discharge from incision, incisional inflammation and vomiting, were infrequent and mild.1
Veterinarians welcome the advances of new therapeutic options, specifically NOCITA to provide local post-operative analgesia for cranial cruciate ligament surgery in dogs. However, Aratana also anticipates providing veterinarians with two additional therapeutics. Earlier this year, the Company also received FDA-approval of GALLIPRANT® (grapiprant tablets) for the control of pain and inflammation associated with osteoarthritis in dogs and ENTYCE® (capromorelin oral solution) for appetite stimulation in dogs.
Over the course of the next year, veterinarians can expect to add these three new tools to their arsenal. Aratana hopes these new tools may help raise the standard of care and close the innovation gapbetween veterinary medicine and human science. Aratana celebrates the opportunity to deliver these therapeutics to veterinarians because not only does it better the lives of the pets we love, but these therapeutics may also mean a new beginning for pet owners.
Drs. Lesley Rausch-Derra, Ernst Heinen, Steven St. Peter and Jessica Wofford celebrate the submission of Aratana’s third administrative NADA filing in 2016.
When Aratana was founded in 2010, onlookers thought one company gaining three FDA approvals just six years after development started was a far-fetched dream. Now, that dream is a reality.
“An FDA approval is what I live for – three, that’s like winning the gold medal at the Olympics,” states Dr. Lesley Rausch-Derra, Aratana’s lead drug developer on NOCITA. “I will forever know that candidates I worked on from the beginning have the potential to help many dogs. It gives my life meaning and makes me proud that we’ve delivered on our promise.”
On a much grander scale, the third FDA approval also validates a concept. The concept that you can take human biopharmaceutical advances and bring them to veterinary medicine. It breaks the barrier that it can be done – and be done well.
“Validating that the innovation model is feasible in animal health is very gratifying,” notes Dr. Steven St. Peter, Chief Executive Officer of Aratana. “I believe in the next few years there will be a move toward growth and innovation in animal health. We are now at the forefront, a pioneer of sorts, of what we hope will advance the industry.”
“For Aratana, this is the fruition of six years of work and contributions from many people in the organization – a true team success.”
1. NOCITA (bupivacaine liposome injectable suspension) Freedom of Information Summary, NADA 141461.
Important Safety Information NOCITA® (bupivacaine liposome injectable suspension) is for use in dogs only. Do not use in dogs younger than 5 months of age, dogs used for breeding, or in pregnant or lactating dogs. Do not administer by intravenous or intra-arterial injection. Adverse reactions in dogs may include discharge from incision, incisional inflammation and vomiting. Avoid concurrent use with bupivacaine HCI, lidocaine or other amide local anesthetics. Please see the full Prescribing Information for more detail.
GALLIPRANT® (grapiprant tablets) Not for use in humans. For use in dogs only. Keep this and all medications out of reach of children and pets. Store out of reach of dogs and other pets in a secured location in order to prevent accidental ingestion or overdose. Do not use in dogs that have a hypersensitivity to grapiprant. If Galliprant is used long term, appropriate monitoring is recommended. Concomitant use of Galliprant with other anti-inflammatory drugs, such as COX-inhibiting NSAIDs or corticosteroids, should be avoided. Concurrent use with other anti-inflammatory drugs or protein-bound drugs has not been studied. The safe use of Galliprant has not been evaluated in dogs younger than 9 months of age and less than 8 lbs (3.6 kg), dogs used for breeding, pregnant or lactating dogs, or dogs with cardiac disease. The most common adverse reactions were vomiting, diarrhea, decreased appetite, and lethargy. Please see full product label or call 1-888-545-5973 for full prescribing information.
ENTYCE® (capromorelin oral solution) is for use in dogs only. Do not use in breeding, pregnant or lactating dogs. Use with caution in dogs with hepatic dysfunction or renal insufficiency. Adverse reactions in dogs may include diarrhea, vomiting, polydipsia, and hypersalivation. Should not be used in dogs that have a hypersensitivity to capromorelin. Please see the full Prescribing Information for more detail.
The Company announced an animal health research and development collaboration with AskAt Inc, including an option agreement for multiple therapeutic candidates with potential in pain, allergy and cancer.