Introduction

Opioids have long been the backbone of acute peri-operative pain. Ironically, it is probably due to their efficacy that the recognition and treatment of acute pain has progressed so rapidly in the last several decades. With that progression in understanding the ugly underbelly of the opioids has gradually been revealed: with addiction, regulatory challenges, and a facilitatory role in the progression of chronic pain.

Although a cast of characters, both in physiology and in human form, make up the problem; if we are to label a single system that underlies it all, it would be the immunologic effect of opioids through toll-like receptor (TLR) expressing cells in the central nervous system, such as glial populations. From this stronghold the addiction and tolerance breed, the immunologic effects multiply, and the seemingly paradoxical hyperalgesia emerge. (S, 2017)

A direct consequence of opioid drug interactions with central immune signaling is addiction to opioid medications, which has reached epidemic proportions in the USA in the last decade. In an attempt to stem the tide of addiction, regulatory agencies are intensifying control on opioid medications, limiting the prescribing duration, reducing the overall availability of these medications on the markets, improving addiction treatment, and improving funding for evidence-based treatments that are non-pharmacologic. An excellent example of this work can be found at www.end-opioid-epidemic.org/wp-content/uploads/2019/01/AMA-Paper-Spotlight-on-Colorado-January-2019_FOR-WEB.pdf. While this regulation is slower to affect veterinary medicine, it does influence availability of opioid medications, and many practitioners have been forced to adopt alternate approaches to acute pain protocols due to these changes. These challenges are going to magnify over time, so developing a skill-set to manage acute pain with less and different opioid medications is a critical task for our profession. A further complication to opioid drug use in dogs and cats includes generally poor absorption of oral opioids due to the robust hepato-enteric recirculation that developed in species that may eat questionable food sources.

Fortunately, these considerations are peaking at time when long-acting local anesthetics have become available, as well as a burgeoning database for the non-pharmacologic pain modalities including acupuncture, physical rehabilitation, laser therapy, and a series of mono-clonal antibody therapies directed at treating pain. (HeatherTick, 2018)

The aspects of opioid medications that we will address today include the previously recognized aspects of sedation, dysphoria and gastro-intestinal effects, as well as the more recently realized aspects of immune modulation and glial stimulation that are critical to understand in the practice of both acute and chronic management of pain in veterinary species.

Undesirable Effects of Opioids

Sedation: This is a common side effect of opioids in dogs that is used to advantage when opioids are administered for premedication, however post-operatively it can result in a reluctance to eat, drink and mobilise. The degree of sedation in dogs depends on the opioid used, with butorphanol providing greater sedation than methadone (when combined with dexmedetomidine).¹ Clinically, methadone alone post-operatively appears to provide greater sedation than buprenorphine.

Dysphoria: In cats, sedation is less common, with dysphoria or mild excitation being more frequently associated with opioid overdose in this species. This may be due to differences in opioid receptor distribution in the brain of cats and dogs. Similarly to excessive sedation, cats that are dysphoric are less likely to eat and drink voluntarily which may hinder their recovery from surgery. Dysphoria can also occur in dogs and has been reported following fentanyl administration during orthopaedic surgery.² Signs of dysphoria can be difficult to distinguish from signs of pain, which is challenging in the peri-operative period because if dysphoria is wrongly mis-diagnosed as pain then the further administration of opioids will worsen clinical signs. Dysphoria is usually best managed by the judicious use of sedation such as a low dose of ACP (10 μg/kg IV) or dexmedetomidine (1–2 μg/kg IV) depending on the cardiovascular status of the patient.

Nausea and vomiting: Nausea and vomiting are well-known opioid-induced effects that may possess peripheral and central components. The mechanisms involved in nausea are extremely complex. Low doses of opioids activate mu opioid receptors in the chemoreceptor trigger zone (CTZ), thereby stimulating vomiting. Alternatively, higher doses of opioid may suppress vomiting by acting at receptor sites deeper in the medulla. The CTZ is in the floor of the fourth ventricle, a location which is considered in the periphery due to its incomplete blood brain barrier. Opioids can directly stimulate the vestibular apparatus, although the mechanism of action is still unknown. It has been postulated that morphine and synthetic opioids increase vestibular sensitivity, perhaps by opioids activating morphine opioid receptors on the vestibular epithelium. Maropitant administered prior to morphine and acepromazine administration has been shown to reduce the incidence of vomiting in dogs.³ Methadone is clinically less likely than morphine to cause overt vomiting in dogs and cats although nausea, manifest as lip licking and salivation is still common.

Other gut effects of opioids: As well as being strongly associated with nausea and vomiting, opioids have other potent effects on gut health generally termed opioid-induced bowel dysfunction (OBD). In the GI tract opioid receptors are mainly expressed on neurons within the myenteric and submucosal plexus and the activation of the μ receptor in neurons within the myenteric ganglia or on nerve terminals innervating smooth muscle cells reduces GI motility resulting in constipation. Increased gut transit time due to constipation can also increase the risk of bacterial translocation, compounded by evidence that morphine can disrupt intestinal barrier function and damages tight junction protein organization. It has also been demonstrated that opioids induce gut microbial dysbiosis.

Immune effects of opioids: The effects of opioids on the immune system are complex and depend on the opioid drug, the duration of administration and the dose. Morphine is the best studied opioid and there are convincing data in animals to show that it has immunogenic effects. It suppresses activity in both the innate and adaptive immune system; for example, morphine will decrease phagocystosis and cytokine production by macrophages, decrease cytokine and chemokine production by neutrophils, and decrease antigen presentation by dendritic cells. Effects on the adaptive immune system include decreased antibody production and MHC-II expression. There is one study in dogs documenting an effect of opioids on immune function.⁴ Despite the wealth of evidence in laboratory animals, there is a lack of randomized controlled studies in man and companion animals to determine whether the immunosuppressive effects of opioids are clinically relevant.

Opioid-induced hyperalgesia (OIH): This is defined as opioid mediated sensitization of pain signaling pathways and is generally induced by the administration of high doses of opioids. There is reasonable evidence in laboratory animals and man to support the presence of this phenomenon, although it has not been reported yet in companion animals.

It is diagnosed in man by an increased opioid requirement to manage pain accompanied by a worsening in pain experience as opioid doses are increased and an increase in pain sensitivity over time. Mechanisms of opioid induced hyperalgesia are complex and multifactorial. The NMDA receptor is linked to OIH, with studies in both animals and humans showing that NMDA receptor antagonists such as methadone and ketamine reduce OIH. Other mechanisms that have been postulated include descending facilitation, microglial activation, and a role for μ opioid receptors on nociceptors. Recommended prevention strategies to avoid OIH in human patients are poorly evidence based but include avoiding the use of remifentanil, switching to opioids with a longer half-life, such as fentanyl; limiting opioid dose by the concurrent administration of non-opioid analgesics and the use of regional anaesthesia techniques.

References

1.  HeatherTick, A. N. (2018). Evidence-based nonpharmacologic strategies for comprehensive pain care: the consortium pain task force white paper. Explore. 14, 177–211.

2.  S, S. M. (2017). Toll-like receptor-dependent negative effects of opioids: a battlebetween analgesia and hyperalgesia. Front Immunol. 8:642.

3.  Trimble T, Bhalla RJ, Leece EA (2018). Comparison of sedation in dogs: methadone or butorphanol in combination with dexmedetomidine intravenously. Vet Anaesth Analg. 45:597–603.

4.  Becker WM, Mama KR, Rao S, Palmer RH, Egger EL (2013). Prevalence of dysphoria after fentanyl in dogs undergoing stifle surgery. Vet Surg. 42:302–7.

5.  Lorenzutti AM, Martín-Flores M, Litterio NJ, Himelfarb MA, Zarazaga MP (2016). Evaluation of the antiemetic efficacy of maropitant in dogs medicated with morphine and acepromazine. Vet Anaesth Analg. 43:195–8.

6.  Declue AE, Yu DH, Prochnow S, Axiak-Bechtel S, Amorim J, Tsuruta K, Donaldson R, Lino G, Monibi F, Honaker A, Dodam J (2014). Effects of opioids on phagocytic function, oxidative burst capacity, cytokine production and apoptosis in canine leukocytes. Vet J. 200:270–5.