Chronic pain

Ketamine infusion

Ketamine, derived from phencyclidine, has been used extensively as an anesthetic agent since the 1960s. At subanesthetic doses, this agent has analgesic effects due to a variety of mechanisms of action. For chronic pain it is thought to reverse central sensitization and enhance descending modulatory pathways; in the acute pain setting the analgesic action is thought to be related to its efficacy as an N-methyl-d-aspartate (NMDA) receptor antagonist. Indications for ketamine infusions include patients at high risk for chronic postsurgical pain and OIH, opioid-tolerant patients, and patients with a history of sleep apnea. Various dosing recommendations for perioperative ketamine have been suggested, and a starting dose regimen is included in Table 28.1 . The American Society of Regional Anesthesia (ASRA), American Academy of Pain Medicine (AAPM), and American Society of Anesthesiologists (ASA) released consensus guidelines for intravenous (IV) ketamine infusions for acute pain management in 2018. Recommendations include limiting IV ketamine boluses to 0.35 mg/kg and infusions to 1 mg/kg for patients who do not have intensive monitoring; patient-specific factors may warrant higher doses. Relative contraindications include pregnancy, and patients with active psychosis, poorly controlled cardiovascular disease, and severe liver disease; ketamine can be used in caution in patients with moderate liver disease. Intranasal (IN) ketamine can be a beneficial adjunct for acute pain management in pediatric patients or those with challenging IV access and can be used for amnesia and procedural sedation. Although patient-controlled analgesia (PCA) is a useful tool for helping manage acute pain, the consensus guidelines concluded that the evidence for ketamine IV PCA as the sole analgesic treatment for acute pain was limited, while more robust evidence supported the addition of ketamine to an opioid-based IV PCA.

Lidocaine infusion

Lidocaine was introduced clinically by Dr. Torsten Gordh, Sweden’s first anesthesiologist, in the 1940s. With the trend toward opioid-sparing perioperative management, systemic infusions have increasingly been used as an adjunct in the management of acute perioperative pain. Reported benefits include reductions in pain, nausea, ileus duration, opioid requirement, and length of hospital stay ( Fig. 28.1 ). The clinical benefits of lidocaine have been reported to exceed its half-life by more than five times (8–24 hours), thus unlikely to be completely explained by its sodium channel blockade action. These long-lasting effects are believed to be secondary to a modulation of inflammatory signals seen during trauma and surgery. In vitro preclinical studies evaluating systemic administration of lidocaine have shown an impact on several inflammatory mediators, including NMDA receptors and calcium channels. Lidocaine inhibits the priming of polymorphonuclear granulocytes (PMNs), which have a crucial role in the release of proinflammatory cytokines and reactive oxygen species. Local anesthetics have been shown to block PMN priming when the cells are exposed for an extended period of time, even at low concentration. Animal studies have also shown suppression of wide dynamic range (WDR) neurons and inhibition of C fibers, which may help explain lidocaine’s antinociceptive actions.

Perioperative lidocaine infusion reduces visual analogue scale (VAS) pain scores in patients who have undergone open or laparoscopic abdominal surgery and decreases opioid consumption. Additionally, it can lead to decreased postoperative nausea and vomiting (PONV) and a reduction in the duration of postoperative ileus. Lidocaine infusion also appears to decrease postoperative pain in prostatectomies, colorectal surgery, and thoracic surgery, and reduce postanesthesia care unit (PACU) opioid requirements and pain scores in several ambulatory surgical procedures. Notably there has been no demonstrated association between perioperative lidocaine infusion and delayed discharge from PACU. Long-term benefits of lidocaine infusions include reduction in the incidence of chronic postsurgical pain after mastectomy and an improved quality of life months after major spine surgery. The current optimal dose of lidocaine is still under investigation, and, although rare, patients should be monitored for potential side effects. An example of a protocol from our institution’s Acute Pain Service can be seen in Table 28.2 . Mild side effects may include visual disturbances and dizziness, while more serious side effects include cardiac toxicity and neurologic changes. Rates of at least 2 mg/kg/hour appear to be associated with a greater reduction in opioid consumption and lower pain scores when compared to lower doses. Monitoring plasma lidocaine levels may help guide dosing to avoid toxic levels (5 μg/mL) and should be considered for patients with hepatic or renal dysfunction who may have decreased metabolism and/or excretion.

Patients with chronic opioid use

OIH refers to increased sensitivity to pain in patients exposed to chronic or acute opioid therapy. It is characterized by worsening pain compared to prior opioid use or the development of new pain without evidence of new pathology. Patients with OIH often report a new onset of generalized, burning pain frequently extending beyond the area of initial discomfort. The physician must exercise caution not to confuse suspected hyperalgesia with inadequate analgesia due to undertreatment. In the latter case, pain reduction should be seen with increasing doses of the medication, whereas in the former further opioid prescribing is largely futile. The mechanism behind this phenomenon appears to be both central and peripheral, and likely results from increased production of nociceptive neurotransmitters, substance P, and calcitonin gene-related peptide (CGRP) within the dorsal root ganglia. There is also sensitization of peripheral nerve endings mediated by excitatory neurotransmitters and activation of the descending signaling pathways leading to up-regulation of spinal dynorphins. In the acute setting, OIH has been mostly reported for patients treated with short-acting opioids, such as remifentanil infusions, with some evidence of elevated pain scores and morphine requirements postoperatively. The precise etiology of OIH with remifentanil when compared to other opioid agonists has yet to be elucidated, but it may be related to its fast onset and offset of action. Meta-analysis of randomized control trials indicates that remifentanil-induced OIH peaks around 1 hour after surgery and may last for up to 24 hours.

In the chronic setting, experimental studies have documented hyperalgesia to heat pain after even just 1 month of opioid therapy. In recent systematic reviews it has been reported that although OIH is evident for patients on chronic opioid therapy, the findings are dependent on the pain modality and assessment measures, with decreased pain tolerance to thermal stimuli but not electrical. Preoperative considerations for these patients include weaning of opioids prior to surgery as tolerated, which is often managed by the patient’s opioid prescriber. A preoperative opioid rotation to reduce adverse reactions while simultaneously maintaining adequate analgesia can also be attempted. Preemptive analgesia to prevent an acute onset of hyperalgesia in the immediate or early postoperative period should be utilized. Ketamine, which has been demonstrated to prevent OIH in both animal and human studies, should be strongly considered along with other strategies, including magnesium sulfate and nitrous oxide. Adding opioid-sparing medications can aid in OIH management while reducing opioid needs. In patients suffering from long-lasting OIH, an opioid agonist with concomitant NMDA receptor antagonism such as methadone or a partial opioid agonist and κ antagonist such as buprenorphine can be alternative pharmacologic options ( Fig. 28.2 ).

Patients on buprenorphine therapy

Buprenorphine is a partial μ receptor agonist and κ and Δ receptor antagonist; it has a high receptor affinity and slow dissociation. It has been available in both sublingual and oral (PO) formulations since the 1970s. In 2000, the Drug Addiction Treatment Act was passed, allowing for qualified physicians to treat opioid addiction with narcotic medications, including buprenorphine. Buprenorphine is also prescribed for the management of chronic pain; therefore not all patients who present to the operating room (OR) on this medication have a history of opioid misuse. A common sublingual combination formulation is buprenorphine coadministered with naloxone, which can be administered in a film or tablet. The most common buprenorphine-naloxone combination is mixed in a 4:1 ratio. Because naloxone has poor bioavailability when taken sublingually, minimal amounts enter the bloodstream when the combined medication is taken appropriately. However, if taken IN or IV, a significantly larger portion of naloxone enters the bloodstream, thereby acting as a deterrent to potential abuse.

Given buprenorphine’s high receptor affinity, it can displace opioid agonists from receptors. The long half-life, up to 6 hours for the IV formulation, and reported analgesic ceiling effect provide further potential for uncontrolled postoperative pain. Patients taking buprenorphine in any form scheduled for elective surgery should be evaluated, and a perioperative plan should be formed in conjunction with their buprenorphine prescriber. A thorough discussion regarding the risks and benefits of either discontinuing or continuing buprenorphine preoperatively must take place. Discontinuing buprenorphine may result in challenging postoperative pain management. Possible risks with discontinuation of buprenorphine include delaying surgery to allow for an adequate taper, opioid abuse relapse, overdose during buprenorphine discontinuation, and opioid withdrawal during reinduction onto buprenorphine. Recent protocols have been published that offer recommendations based on the urgency of surgery and the level of anticipated postsurgical pain; the majority recommend continuing buprenorphine through the perioperative period. Other recommendations include tapering doses down to 12 to 16 mg/day and returning to preoperative doses as soon as possible.

Managing acute pain in patients who are on buprenorphine can present a unique challenge. The US Center for Substance Abuse Treatment (CSAT) stated in the Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction: Treatment Improvement Protocol (TIP) report that “it may be difficult to achieve analgesia with short-acting opioids in patients who have been maintained on buprenorphine, and higher doses of short-acting opioids may be required.” They recommend noncombination opioid analgesics given the potential risk of salicylate or acetaminophen toxicity when administering these medications at the higher doses, which are likely required for patients on chronic opioids. The clinical practice guidelines from ASRA, the ASA Committee on Regional Anesthesia, and the American Pain Society provide recommendations that should be strongly considered in these patients. They include the use of multimodal analgesia with both pharmacologic and nonpharmacologic interventions, PCA for postoperative systemic analgesia when a parenteral route of opioids is needed, and single-injection or continuous regional analgesia when possible ( Box 28.1 ).