Opioids

Opioids have a long history in medicine dating back to the opium flower. Overtime, opioids have fallen in and out of favor for pain control, particularly post-operatively. In the past decade or two, we have unfortunately seen the rise of opioid-related deaths leading to an opioid epidemic of addiction and overdoses in the United States and worldwide. As dangerous as these medications can be, they maintain a crucial role in providing analgesia for surgical patients. In anesthesia, we administer opiates all the time for our patients, however, very calculated and cautiously. Based on the type of surgery, patient history, and post-operative plans, we layer narcotics into our multi-modal intraoperative post-operative analgesic plan. With a multimodal pain plan, you can limit how much narcotic a patient requires, reducing the side effects that come with these medications. The rise of regional anesthesia and nerve blocks has also reduced the amount of opioids use in the perioperative period. And although we typically think of opioids as a post-operative medication, we also use them as a pre- and intra-operative medication.

Opioids create an effect by acting on opioid receptors found all over the body. One way to classify opioids is based on their interaction with their receptors: agonists, partial agonists-antagonists, and antagonists. The three main opioid receptor subclasses that we commonly focus on for their desired effects are mu-, delta-, and gamma-opioid receptors. These receptors are made up of 7 transmembrane proteins that couple with G-proteins and lead to downstream ion channel modifications. These modifications usually result in changes in ion transport (ie. potassium, calcium) that lead to hyperpolarization of the membrane and reduced pain transmission from the periphery to the central nervous system. Although these receptors are found all over the body, the sites that primarily lead to analgesic and sedative effects include periaqueductal grey, rostral ventral medulla, locus coeruleus, and substantia gelatinous.

Part of the versatility of opioids is many routes of administration you can use. As anesthesiologists, we primarily use the intravenous route. However, they can also be administered orally, enterally, transdermal, subcutaneously, neuraxially, and aerosolized. When using an IV, it can either be given via boluses or by continuous infusion.

Because opioid receptors are found ubiquitously in the body, there are many side effects that come with opioid use. Starting with the central nervous system, you can see sedation, euphoria, miosis, and pruritis (itchiness). In the cardiovascular system, you can see bradycardia and vasodilation, both potentially leading to hypotension. Ventilatory response to hypercarbia and hypoxia decrease, with a decrease in baseline minute ventilation as well. In the gastrointestinal system, you can see delayed gastric emptying, increased biliary pressure, and constipation. In the genitourinary system, it is possible to see urinary retention. And in the musculoskeletal system, large dose of opioids can lead to muscle rigidity.

Opioids can be categorized into 3 categories based on their action on their respective receptors: agonists, antagonists, and partial agonist-antagonists. 4 most commonly used agonists in the operating room include morphine, fentanyl, hydromorphone, and remifentanil. The most commonly used antagonists use in the perioperative field is naloxone. And the partial agonist-antagonists are used more commonly in the outpatient setting for patients with chronic pain or opioid addiction.

Morphine is considered the parent drug of all other opioids and is naturally produced in nature. Since its discovery, it has proven to be a very effective remedy for pain. However, its histamine-related side effects (ie. hypotension, pruritis) lead to the development of synthetic opioids, like fentanyl. Morphine has a slow onset of action due to its highly ionized state and its low lipid solubility. This leads to slow penetration of the CNS. While this decreases the risk of acute respiratory depression, it is important to wait a sufficient time before re-dosing morphine. The other important consideration with morphine is it has an active metabolite, morphine-6-glucuronide. This metabolite plays a role in providing analgesia. The issue arises in kidney failure patients since this is excreted renally and thus has potential to accumulate when morphine is used in these patients.

Fentanyl is one of the most useful opioids in modern anesthesia practice. It’s versatility provides an array of uses for it. We typically administer it by IV, however it can also be given transdermal, transmucosal, transnasal, and transpulmonary. When given IV, it has a fast onset of action and a relatively short duration of action. It does have a very long context-sensitive half life which leads to a prolonged tail after stopping an infusion that has been running for longer than a couple of hours. When given in boluses, it can be carefully titrated to a patient’s respiratory rate when they are breathing spontaneously or on pressure support on the ventilator.

Hydromorphone (Dilaudid) is the most commonly used opioid for post-operative patient control. You can also use it intraoperatively for procedures that will be consistently painful. This will reduce the amount of inhaled anesthetic needed during the case (reduced MAC). It can take about 15 minutes for its onset of action to take place. Hydromorphone has a metabolite like morphine, hydromorphone-3-glucuronide. It has no analgesic effect but can lead to potential seizures if it accumulates. Unlike morphine, you do not see histamine-related reaction with hydromorphone.

Remifentanil is one of the most ideal anesthetic drugs given its quick onset and fast recovery. Its fast recovery is due to its metabolism by plasma esterases. This process is independent of hepatic and renal function. We most commonly use it as an infusion in the operating room in patients who require no movement without paralysis (ie. neurosurgical cases with neuromonitoring). It also is used for “smooth” wake-ups to prevent any coughing or bucking on the endotracheal tube which could lead to bleeding after surgeries around the neck or head. You can also use remifentanil as a bolus for stimulating portions of a procedure, such as laryngoscopy or headpin placement. This will almost always lead to bradycardia and hypotension. Ephedrine is a good choice to treat this side effect. After stopping the infusion, it is common for patients to develop opioid-induced hyperalgesia. This is commonly seen in infusion doses greater than 0.2 mcg/kg/min. You must remember to give a long acting opioid if using remifentanil as an infusion for a painful procedure

Buprenorphine and Nalbupine are mixed agonist-antagonists. Buprenorphine can be given sublingually, transdermally, or parenterally. Moderate doses can be used to treat chronic pain. The antagonist effects of Buprenorphine can be overcome with high dose opioid agonists. Nalbupine has a potency and duration of action close to morphine’s. It can be used as a reversal agent for opioid-induced ventilatory depression while at the same time providing some analgesia.

Nalaxone is a pure antagonist that is used as an emergency drug to reverse the ventilatory depressive effects of opioids. This is commonly seen in opioid overdoses. It also has some potential benefit in opioid-induce pruritis. Although it is very effect in reversing the action of opioids, it also comes with some unwanted side effects that look like acute withdrawal. These include nausea, vomiting, tachycardia, hypertension, seizures, and potentially pulmonary edema. The key thing to remember is that nalaxone’ s duration of action is shorter than most opioids. Therefore, when giving nalaxone, you must watch the patient for at least a couple of hours to see if you need to re-dose it before the underlying opioid has finally been cleared.