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Second, morphine induced no analgesia in these patients, even at very high plasma concentrations. In other words, the patients were completely tolerant to the analgesic effects of morphine, but only partially tolerant to the respiratory depressant effects of the drug.
Therefore, although more data in humans are required, differential opioid tolerance is appears to be a clinically relevant phenomenon. Patients using chronic opioids are often profoundly tolerant to analgesic actions of the drugs and will require increased doses of opioids to provide adequate postoperative analgesia.
However, only limited tolerance to the respiratory side effects of opioids has developed in these patients. They are, therefore, at increased risk for respiratory depression. To prevent adverse outcomes postoperatively, these patients require close monitoring after surgery.
Providing supplemental oxygen may prevent hypoxia when ventilation is depressed but also will prevent any protective effect of the HVR, which is increased in patients receiving chronic opioids. Supplemental oxygen will also reduce the usefulness of Sa o 2 monitoring.
In addition to the concerns associated with differential tolerance to opioids, clinicians also need to consider the development of OIH in their patients. Although the clinical relevance of this phenomenon during the perioperative period is somewhat controversial, several studies have demonstrated increased opioid requirements and worsened pain scores in patients exposed to high-dose intraoperative opioids.
The difference between acute opioid tolerance and OIH is conceptually easy to understand, but the two are clinically difficult to separate.
OIH is defined as the increased sensitivity to painful stimuli as a result of opioid use. Tolerance is defined as a requirement for increased doses of an opioid to achieve the same analgesic effect. In clinical practice, the development of either of these phenomena will lead to increased pain, with the usual consequence of escalating doses of opioids.
Whether the increased opioid requirement is caused by lowering the pain threshold, as in OIH, or by decreasing the potency of the drug, as in tolerance, the clinical effect is the same. They appear to have a dose—response relation and as such the magnitude of tolerance or OIH in the setting of high-dose opiates is increased. The concept of OIH has been recognized for over yr. These include activation of adenylate cyclase, N -methyl- d -aspartate NMDA -type glutamate receptor activation, and release of pronociceptive peptides such as dynorphin A and neuropeptide FF.
According to this theory, the pronociceptive response is delayed or masked by analgesia after administration of an opioid but increases when repeated doses are administered. Hence, one initially expects to see analgesia in response to opioid administration, but increasing pain will develop with repeated doses.
Six groups of rats were randomized to receive either subcutaneous saline injections or various doses of fentanyl. Their pain threshold was determined at baseline using a paw-pressure vocalization test. They then received saline or fentanyl injections subcutaneously every 15 min for a total of four injections, and the pain threshold tests were repeated over the next few hours until evidence of analgesia disappeared.
The examiners then repeated the tests daily for the next 5 days. All rats that received fentanyl developed OIH meaning that on posttrial day 1, all rats had a decreased pain threshold from baseline.
OIH persisted much longer than the duration of analgesia, with the rats that received the highest dose of fentanyl demonstrating OIH for 5 days. No change in pain tolerance was observed in rats that received saline. This study not only demonstrates robust OIH development after opioid administration but also shows that it can develop within a very short time, comparable to the length of the perioperative period. It is hard to extrapolate these data for human clinical use, but it serves as an illustration of the concept of OIH.
Similar findings, however, have been confirmed in humans. As mentioned, separating tolerance and hyperalgesia is difficult in the clinical setting. In addition, the type of pain that is aggravated wound hyperalgesia vs. It has been demonstrated that wound hyperalgesia the size of the area of hypersensitivity surrounding a wound specifically has an effect on long-term pain.
Salengros et al. After measuring the area of wound hyperalgesia, he showed that its size was increased by higher doses of IV opioids, and the extent of wound hyperalgesia corresponded to an increased risk of chronic pain at 3, 6, and 9 months.
Guignard et al. Patients were randomized to receive either a high-dose or low-dose remifentanil infusion throughout the procedure; the remainder of the anesthetic was standardized. On average, the patients receiving high-dose remifentanil receiving on average 0. This same phenomenon has been shown with remifentanil in children 12 and with fentanyl in adults. Several studies were unable to demonstrate evidence of OIH after intraoperative opioid administration.
For example, in women undergoing gynecologic surgery, no difference was found in pain scores between groups receiving sevoflurane anesthesia versus sevoflurane and a remifentanil infusion. In addition, the average dose of remifentanil was moderate and, therefore, would likely show a lower demonstrable effect of OIH. A recent meta-analysis of postoperative OIH by Fletcher and Martinez 25 took these negative studies into account and still demonstrated that high-dose approximately 0.
This meta-analysis included 21 randomized, controlled trials of intraoperative remifentanil, most of which were published after The meta-analysis also included two studies of fentanyl and one of sufentanil. These opioids did not seem to induce OIH, but obviously the data set is limited. It is reasonable to expect that all opioids would function in the same manner, activating pronociceptive systems, although in recombinant models remifentanil has been suggested to have additional actions, such as direct activation of NMDA receptors.
There are also some limited data to suggest that intrathecal opioids can cause OIH 27 although much more study is needed to investigate that route of administration. One study not included in the meta-analysis evaluated the use of remifentanil versus esmolol versus fentanyl during the laparoscopic cholecystectomy. The remifentanil and fentanyl groups showed increased requirement for opioid in the postanesthesia care unit compared with the esmolol group. Postoperative fentanyl requirements were Patients receiving esmolol also were discharged from postanesthesia care unit earlier than patients receiving opioids.
Although other explanations are possible e. Postoperative opiate requirements in patients receiving esmolol, fentanyl, and remifentanil intraoperatively. Amounts of fentanyl required in the postoperative care unit PACU to provide adequate analgesia in patients who underwent laparoscopic cholecystectomy.
The use of intraoperative opioids is associated with an increased postoperative opioid requirement. Modified from Collard et al. Anesth Analg ; — The best way to address OIH or acute tolerance will likely be prevention. For this reason, it is prudent to consider alternative opioid-sparing adjuncts when possible, in an effort to reduce the opioid use for patients under general anesthesia.
Peripheral nerve blocks and neuraxial anesthesia can reduce the need for opioids and have an opioid-sparing effect. In addition, although usually expensive, drugs such as esmolol 28 and dexmedetomidine 29 can approximate the effect of opioids on heart rate, blood pressure control, and volatile anesthetic requirement. However, many patients will still require opioids perioperatively, and occasionally, chronically.
The data available on differential opioid tolerance and OIH, although not absolutely conclusive for the perioperative setting, suggest that it would be prudent to craft an anesthetic that incorporates nonopioid adjuncts and not solely depend on intraoperative opioids for the provision of postoperative pain relief. Patients using very high doses of opioid analgesics preoperatively may not be protected from adverse events by tolerance development, and this group may be at particular risk.
Perioperative opioid administration may render subsequent opioid analgesic administration less effective and might lead to OIH or acute tolerance. Still, many patients will undergo surgery of such magnitude that opioids will be required for postoperative pain control. A multimodal approach with a variety of other modalities, including NMDA receptor blockers and regional nerve blockade, can limit the opioid requirements.
The number of opioids prescribed in the U. Acute pain may present postoperatively because of the traumatic surgical injury, or in other acute conditions. Acute pain in patients with opioid tolerance makes pain management a challenge, and perhaps one of the greatest risks associated with pain management in this population is the risk of undertreatment due to stigma and bias. Further, data on pain management in this patient population are limited.
The sensation of pain occurs via nociception , a process of communication between the site of tissue damage and the central nervous system CNS. Neuropathic pain differs from nociceptive pain in that neuropathic pain results from abnormal processing of nerve impulses in the peripheral nervous system and CNS, whereas nociceptive pain results from noxious stimulation of free nerve endings in the tissue.
It is theorized that, with chronic opioid exposure, extensive adaptations occur at the cellular and synaptic levels, leading to opioid tolerance.
A condition that overlaps with opioid tolerance is opioid-induced hyperalgesia OIH. However, the difference between them is that in opioid tolerance, an increased amount of opioids is necessary to relieve the pain, whereas in OIH, the same amount of opioid causes paradoxically worse pain. Pain is subjective, which makes it difficult to assess the degree of severity. Generally, acute pain is a multidimensional experience, usually resulting from trauma, that lasts no longer than 3 to 6 months, but it has the potential to become more complex, both physiologically and psychologically.
Uncontrolled pain affects various systems, including the CNS and the cardiovascular, pulmonary, gastrointestinal, renal, immunologic, and muscular systems. Additionally, overall recovery is significantly affected, and progression to chronic pain pain that is persistent in nature, lasting longer than 6 months may result. This comorbidity is associated with a greater burden to the patient than for either condition alone.
As outlined in the clinical practice guidelines, goals for acute pain management include 1 early intervention, with frequent regimen adjustments for uncontrolled pain; 2 reduction of pain to an acceptable level determined by the patient; and 3 facilitation of recovery from the underlying disease or injury.
It is also important to aim for prevention of adverse drug events and opioid-withdrawal symptoms; improved quality of life; and assistance with any social, psychiatric, or behavioral components that may hinder effective pain management. Acute pain management in opioid-tolerant patients often requires a multimodal and multidisciplinary approach; therefore, it is necessary to maintain careful coordination and effective communication between disciplines, as well as between each discipline and the patient.
As with the general patient population, a multimodal pain regimen with a combination of pharmacologic and nonpharmacologic approaches is ideal.
Opioids remain the drug of choice for severe pain and are a common option for moderate pain, but multimodal pain management with acetaminophen, nonsteroidal anti-inflammatory drugs NSAIDs , and adjuvant medications TABLE 1 remains the mainstay of effective analgesia. In order to prevent delays in care and the risk of untreated pain, analgesics should be administered on a scheduled basis rather than an as-needed basis.
Opioid-related side effects are less common in opioid-tolerant patients; however, if opioid therapy is selected as analgesia of choice in these patients, monitoring for side effects or complications related to opioid therapy remains just as important as with the general population. In the selection of opioids as analgesia of choice, patient-controlled analgesia PCA offers a convenient method of delivery, as it minimizes the risk of undertreatment, allows self-titration, and negates possible conflicts with nursing staff.
Opioid withdrawal can occur in opioid-dependent patients receiving a reduced amount of their usual opioid or using an opioid antagonist. The Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition, lists four criteria for opioid withdrawal: 1 previously heavy and prolonged opioid use ceases or is reduced, or an opioid antagonist is administered after a period of opioid use; 2 at least three signs and symptoms e.
Similarly, this approach should be employed in maximally tolerated doses in opioid-tolerant individuals. The number of people worldwide aged 65 years and older was estimated at million in , and by that number will increase to 1. According to the CDC, more than 2. Older adults are frequently untreated or undertreated for pain. A predictable age-related decline in CYP function plays a major role in drug metabolism.
In addition, polypharmacy is a well-known issue in this population. Multidisciplinary and multimodal approaches to treatment are recommended to optimize treatment response without jeopardizing safety. It is also important to consider the frailty of older adults and the risk of falls. The medication lists of all older adults should be reviewed comprehensively for drug interactions and CNS-altering agents.
In , the Beers Criteria were updated to note that opioids should be avoided if the patient has a history of falls and fractures or is taking three or more CNS-active drugs concomitantly, which increases the risk of falls.
Additionally, an understanding of the different types of pain nociceptive vs. Adjuvants and topical agents are ideal for geriatric patients to reduce the opioid requirement and associated risks. Opioid misuse and dependence among prescription-opioid patients continues to rise in the U. Opioid addiction is driving this epidemic, with 20, overdose deaths related to prescription pain relievers. These risk factors have also been noted to promote perceptions among healthcare providers that can lead to the undertreatment of true pain.
Given the growing epidemic of opioid abuse and misuse, several state boards of pharmacy have implemented prescription-monitoring programs that can help providers identifying aberrant behaviors in the acute-care setting. Additionally, the FDA is encouraging the development of opioid formulations with abuse-deterrent AD properties and mixed agonist-antagonist opioids TABLE 3 to help combat the opioid epidemic. However, most of these newer formulations are extended-release ER and are more appropriate for patients requiring long-term opioid use.
The FDA notes that long-acting and ER opioid formulations are appropriate only for opioid-tolerant patients. Increasing numbers of patients with opioid addiction are receiving opioid agonist therapy OAT with methadone and buprenorphine, and some are receiving OAT combined with naloxone or simply naltrexone alone. Naloxone and naltrexone are pure opioid antagonists that block all types of opioid receptors; they can be orally administered and have a long duration of action.
As a result, providers will more frequently encounter OAT patients who have developed painful conditions that need effective treatment strategies.
Long-term OAT patients are at increased risk for pain undertreatment.
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