Pain Medications and Canine Immune Function

The following interview was originally released as a podcast on June 6, 2013.  If you prefer to listen to the interview, the podcast is available here. Additionally, a glossary of some of the scientific terms used in the interview is provided at the bottom of the page.

In this interview, Dr. Amy DeClue, Assistant Professor of Small Animal Internal Medicine at the University of Missouri College of Veterinary Medicine, provides a research update on her CHF-funded grant which investigates whether any of the common pain medications used in dogs could inadvertently suppress the immune system, leaving dogs susceptible to infection after surgery or a major procedure.

AKC CANINE HEALTH FOUNDATION (CHF):  Can you describe the common medications used to treat pain in dogs?

DR. AMY DeCLUE:   The most common medications we use are non-steroidal anti-inflammatory drugs or NSAIDs and opioids. Opioids are the strongest class of pain medication and they provide the best pain relief. Of the opioids there are drugs that are complete opioid receptor agonists, drugs like morphine, fentanyl, and tramadol. There are also partial agonists, drugs like buprenorphine. Each drug is a little bit different, has different potential side effects, and is administered in different ways.

CHF: What are some examples of when these drugs would be used?

DeCLUE:  Opioids are used on a routine basis in a variety of situations and are used in almost all anesthetic and analgesic protocols for animals undergoing surgery, including spays and neuters and orthopedic procedures. Opioids are also used to manage pain associated with cancer and they're a very important part of managing orthopedic disease. As you know, sports related injuries and osteoarthritis, are common problems in our canine athletes. Opioids are important for managing the pain associated with these problems, as well as managing the pain injury, especially after the injury, or during physical therapy and sports rehabilitation.

CHF:  What led you to believe these drugs might affect the immune system?

DeCLUE:  Opioids are actually made by the body, and opioid receptors are found on almost all types of immune cells, suggesting that endogenously produced opioids help signal the immune system. The opioids we use for pain management can bind and signal through the same receptors as endogenously produced opioids. This means that the opiate medications we give to dogs to help manage their pain could affect the immune system. Additionally, there's some work in rodents and some evidence in people that opioids alter immune function.

CHF:  Your CHF grant focused on the three major indicators of immune function: cytokine function, cytolytic function of macrophages and neutrophils, and respiratory burst function of neutrophils. Can we take these individually and can you explain why they're important parameters of immune function? Let’s start with cytokines why do they matter?

DeCLUE:  When a white blood cell identifies danger, let's say from an invading bacteria, the first response is to send out a message to the other white blood cells. This message summons the white blood cells to the site of conflict and helps activate them. Cytokines are that message. Cytokines make up the communication system for immune cells so that there's an orchestrated attack that the body's making. The cytokines are also important for stopping the immune reaction once the threat has been cleared. It's through the use of these messages, or cytokines, that the immune system becomes activated and also returns to rest. Cytokines help maintain the balance and communication within the immune system.

CHF:  What is phagocytosis and why does this matter?

DeCLUE:  Phagocytosis is the process by which white blood cells engulf foreign material, like bacteria. This prevents the bacteria from multiplying and spreading. So phagocytosis, in a way, is one of the first lines of defense against infection.

CHF:  And finally, what is respiratory burst and why does it matter?

DeCLUE:  After bacteria invade the body the white blood cells have to be able to kill them. The white blood cell puts bacteria into a special compartment and then the white blood cell produces toxic chemicals, things like peroxide and bleach, and injects these chemicals into that special compartment to kill the bacteria. This is called respiratory burst. It's a highly effective means for clearing infection from the body.

CHF:  Going back to your CHF grant, how exactly did you conduct your study?

DeCLUE:  We collected blood from six healthy adult dogs and we used that blood to study the effects of several opioids on immune function. The opioids we studied were morphine, fentanyl, buprenorphine, and tramadol. We also studied O-desmethyltramadol which is the active metabolite of tramadol.

CHF:  What were the results of your study, beginning with tramadol and O-desmethytramadol?

DeCLUE:   We found that tramadol and O-desmethytramadol did not affect phagocytosis or respiratory burst function. However, we found that O-desmethyltramadol, which is the active metabolite of tramadol in the body, decreased the production of a key anti-inflammatory cytokine. This could be important because the anti-inflammatory cytokine helps regulate inflammation and prevent an over zealous inflammatory response. Anti-inflammatory cytokine's also help turn off the immune system at the end of the inflammatory response. Of course we have to be cautious about over-interpreting these findings. This is what happens in a test tube. Before we make any changes in how we use drugs in dogs, we need to see if tramadol and O-desmethytramadol effects the anti-inflammatory cytokine production actually in the body.

CHF:  What were the results when you considered the effects of morphine, fentanyl and buprenorphine?

DeCLUE:  None of these opioids altered immune function. However, morphine increased respiratory burst activity in neutrophils. Morphine, fentanyl and buprenorphine all promoted cytokine production, both pro-inflammatory cytokines and anti-inflammatory cytokines. This tells us that all of these opioids are able to alter immune function, but that morphine has the most dramatic effect. These findings can mean that morphine helps activate the immune system and can prevent or can clear infection. It may also mean that morphine could promote inflammation which could be damaging. Again, we're looking at what happens in test tubes, and we need to see what happens inside the dog. These initial findings help us know which pathways are most likely to be effected so we can target our future investigations in the most appropriate pathways in dogs.

CHF:  Did you expect to see a differential effect of these medications on the immune system?

DeCLUE:  Since each of these medications has a different structure and different receptor binding characteristics, we did expect to see some differences.

CHF:  And given your results does this change your recommendation for using certain drugs in certain situations?

DeCLUE:  The information we have currently is very preliminary. Again, this is what happens in a test tube and it doesn't necessarily mean that's what happens in a dog. Before changing clinical practice, we must do more research. Managing pain is very important. In fact, pain itself has major effects on the immune system. For now, the focus will remain on providing excellent pain control for our patients. We will also pursue further research to determine how opioid selection can be used to strategically alter the immune response in dogs that potentially have inflammatory conditions.

CHF:  As we continue to fund canine research in both immunology and pain management, where do you think our greatest gaps in knowledge are and what type of research do we need to fund?

DeCLUE:  First, I want to emphasize the importance of understanding the effects of opioids. Opioids are some of the most commonly prescribed medications. In fact, millions of dogs receive opioids every year. When they're used it's typically in a population of dogs that is at risk for infection or immune system violated problems like severe inflammation. Learning more about how to select the best opioids not only enables effective pain management, but also stands to enhance our understanding of the immunological affects which will have widespread benefits for dogs. This initial study has allowed identification of key pathways for further investigation. My lab is working on the next steps in the process. This will include expanding our evaluation of the effects of opioids on additional immunologic parameters and evaluating the effect of opioids on the immune system after they are administered to a dog (i.e. not limiting our studies to the effects of opioids on cells in a test tube). Then, we need to evaluate how opioids alter immune function in dogs with common illness, dogs that have surgical trauma, or dogs with orthopedic disease. Finally, once the best candidate drugs are identified, clinical trials can determine the impact of opioid selection on things like critical illness, cancer, surgery, and orthopedic disease. For now, my colleagues and I are continuing this line of research and we greatly appreciate the AKC Canine Health Foundation for their support. We hope that our results will pave the pathway for future discovery in improved animal health.

Glossary of terms for this podcast:

Cytokine: Soluble proteins used as messengers between cells that can either activate or suppress the immune response.

Macrophage: Cell of the immune system used to engulf and destroy invading pathogens.

Neutrophil: Cells that are the first line of defense of the immune system; they can engulf and destroy invading pathogens or release toxins that destroy pathogens. The release of toxins can also cause collateral damage to healthy tissue and cells.

Phagocytosis: The act of a macrophage or neutrophil internalizing (“eating”) foreign bacteria.

Cytolytic: Term used to describe the destruction of infected cells by toxins released from cells of the immune system.

Inflammation: The outcome of an immune response, as cells of the immune system respond to an invading pathogen they cause collateral damage to healthy cells, causing pain, heat, redness and swelling.

Respiratory Burst: The events that occur inside a macrophage or neutrophil that lead to destruction of engulfed bacteria.

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