Opioids have been the cornerstone of the development of modern veterinary anaesthesia and analgesia. Gone are the times when pain served the purpose of “protecting the surgical site” from excessive use. Luckily, we have now moved away from the “no pain, no gain” approach to pre-operative analgesia, at least in small animals. Opioids have been a lifeline for veterinary anaesthetists when administering pre-anaesthetic medication, inducing anaesthesia and providing post-operative analgesia, even in the sickest animals.
I cannot think of many conditions in which animals are deemed not to be sufficiently fit to receive an opioid analgesic. Thanks to opioids, we can now perform very invasive procedures and can relieve post-operative pain until animals can be discharged and sent home. As veterinary anaesthetists, we are particularly lucky because side effects of opioids in animals are generally very mild compared to people. It is objectively difficult to overdose a dog with an opioid, and in the past 15 to 20 years, analgesic protocols for species more sensitive to the behavioural side effects of opioids, for example cats and horses, have been developed successfully.
Opioids are such a relevant part of our daily anaesthetic routine that we now have dedicated veterinary products covering most of our needs, from a short-acting full agonist, to longer-acting full and partial agonists. It is unquestionable that the overall effect of increased opioid use on quality of perioperative care has been positive. The big question is: at what price?
Side effects of opioids
Less obvious, but more insidious, side effects of opioids have been investigated in people and in experimental animals suggesting that, under certain conditions, they may induce hyperalgesia (increased sensitivity to pain) and even contribute to metastatic spread of cancer.
While the effects of opioids on immunity have been investigated in people, little is known about the effect of perioperative opioid use on metastatic rate after cancer surgery in animals. Opioid-based perioperative analgesia increases the risk of cancer recurrence and metastasis in breast and prostate cancer, compared to perioperative analgesia protocols based on locoregional anaesthesia.
The exact mechanisms underlying the pro-metastatic effects of opioids in certain types of cancer are not fully understood. However, immune cells, endothelial cells and tumour cells express opioid receptors, and greater expression of the mu opioid receptor in some tumours has been linked to poorer outcomes.
Administration of physiological doses of morphine triggers intracellular events that promote angiogenesis, mitosis and therefore tumour growth, at the same time decreasing the activity of natural killer cells. While knowledge of the clinical relevance of this is currently limited in animals, its importance is such in people that “opioid free” anaesthetic techniques are becoming more and more common, and new non-opioid analgesic agents are currently being investigated.
how could a drug that reduces pain increase sensitivity to pain?
Opioid induced hyperalgesia (OIH) has been long recognised, yet poorly characterised clinically, and has baffled medics and scientists; how could a drug that reduces pain increase sensitivity to pain? Recognition of OIH in a clinical setting is not unequivocal, as persistent pain may simply be the effect of inadequate analgesia, rather than the manifestation of a more elaborate biological phenomenon.
OIH is a distinct entity from tolerance, although the two share some common molecular mechanisms. Tolerance manifests itself as decreased sensitivity to analgesic effects of opioids, usually due to long-term treatment, and increasing the administered dose restores analgesia.
OIH, on the other hand, is characterised by pain sensitisation and cannot be reversed by increasing opioid dose. Experimental animal models have demonstrated increased sensitivity to pain after administration of various opioids and using different routes. Acute administration of high doses of opioids to rodents results in a biphasic response, initially characterised by analgesia, and then followed by hyperalgesia. Similarly, chronic treatment with opioids results in progressive hyperalgesia.
Increased sensitivity to pain has also been reported in patients undergoing clinical procedures and receiving high doses of opioids during surgery, in former opioid addicts and in normal volunteers. While in the first and second cases the described phenomenon could have been tolerance, OIH has been well characterised in normal volunteers receiving the ultra-short-acting opioid remifentanil.
It is plausible that administration of opioids for prolonged periods, in the absence of pain, or at high doses (perioperatively), may interfere with the balance between the endogenous pro and antinociceptive systems, resulting in OIH. A genetic basis for response to opioids, development of tolerance and OIH has also been postulated. Therefore, the same analgesic regimen may not consistently result in tolerance and OIH.
Should our approach to treating pain change?
Looking into our clinical practice, we can probably all agree that the need to use large doses of opioids in animals in pain is often a predictor of inadequate analgesia. The simple interpretation of this phenomenon has traditionally been that the pain was so severe that the opioid dose used was inadequate, or that other pain mechanisms were involved. Therefore, in these cases we often resort to using ketamine or medetomidine/dexmedetomidine infusion with opioids, with better results.
Interestingly, both tolerance and OIH can be alleviated by administration of NMDA antagonists, for example ketamine, implying a role of NMDA receptor and the glutaminergic system in establishing and maintaining both phenomena. Similarly, alpha-2 agonists may attenuate OIH, suggesting that the adrenergic system is involved in establishing and maintaining OIH.
It is therefore fair to ask whether we have been approaching treatment of pain correctly or, despite our genuinely good intentions, we have been treating moderate to severe pain with drugs that may rapidly cause OIH.
Should we move away from the postulate “more pain, more opioids”? Should we use less opioids and only when needed, resort to alternative analgesic techniques (ie locoregional anaesthesia) to provide a truly preventive analgesia?
Poor analgesia results in peripheral and central sensitisation, causing hyperalgesia, and persistent pain negatively affects functional recovery after surgery. On the other hand, excessive administration of opioids may equally result in hyperalgesia. This fits well within a framework considering a dynamic balance between facilitation and inhibition of nociception, affected by events occurring in the dorsal horn of the spinal cord, with both persistent nociception and excessive opioid administration perturbing the balance. In this perspective, the best approach is preventing nociceptive stimuli from reaching the dorsal horn of the spinal cord, and this can only be achieved with a well planned and executed locoregional anaesthesia. Publications are starting to appear in veterinary medicine, suggesting that complete reliance on perioperative opioid analgesia may not be the best option, despite still being considered a gold standard.
Locoregional anaesthesia proved to be more effective in blunting stress response and resulted in lower perioperative pain scores immediately after surgery. Another recently published study suggested that administration of methadone at regular intervals after TPLO in dogs in which a locoregional technique was used to provide intraoperative analgesia, was associated with decreased food intake, increased incidence of vomiting and behavioural changes (vocalisation, restlessness). This led, in some cases, to observers believing that the dog was in pain. Such side effects were not observed when methadone was administered to dogs, only if needed, according to a validated pain score. Case reports of opioid free perioperative analgesia are also now appearing in published veterinary medicine.
The time to ditch opioids has not come yet, but there is growing evidence that they should no longer be considered the gold standard for perioperative analgesia. Opioids still have an unquestionable place in veterinary analgesia, but we should probably not rely upon them as if they were a panacea for pain. Instead, we should develop a more critical approach to perioperative analgesia.
