A 28-year-old woman with osteosarcoma presented for excision of a mediastinal mass under general anesthesia. She underwent left hemipelvectomy approximately 2 years ago. There was no other significant medical history. Her symptoms consisted of allodynia over her left lower extremity with radicular symptoms in an S 1 distribution and somatic pain in the left pelvis and hip area. Her current medications included methadone, 10 mg orally every 4 hours, and hydromorphone, 8 mg every 2–3 hours for breakthrough pain. Additionally, she stated she “needed” to take hydromorphone and oxycodone, which she obtained from her sister, who had back pain.
Is this an appropriate analgesic regimen before surgery?
Using long-acting and short-acting opioids for breakthrough cancer pain has been the mainstay of therapy for chronic malignant pain for >4 decades. This concept began with the World Health Organization “analgesic ladder” for treating moderate-to-severe pain associated with malignancies. Methadone pharmacokinetics allows for two or three times daily dosing to provide analgesia; however, its metabolic half-life is 72–96 hours with a bioavailability of almost 98%, and this has to be taken into account when dosing methadone more than three or four times daily. Dosing methadone every 4 hours, as in this patient, not only predisposes to toxic effects such as respiratory depression but also has the potential for rapid development of tolerance and hyperalgesia. More recent guidelines published in the Annals of Internal Medicine recommend a baseline electrocardiogram for all patients started on methadone treatment and ongoing cardiac evaluation, especially for patients with multiple comorbidities or who are treated with drug classes known to prolong Q–T intervals. Numerous case reports exist of life-threatening arrhythmias associated with the use of methadone.
Breakthrough cancer pain can be treated with any short-acting opioid such as hydromorphone or oxycodone depending on the individual genetic profile of opioid receptors and CYP450 metabolism. One of the biggest challenges in treating cancer breakthrough pain is the ability to ensure fast and effective analgesia. Most opioids, such as morphine and hydromorphone, achieve an onset of action within 15–20 minutes when administered orally. Almost complete plasma metabolism occurs within 3 hours. In cases where a more rapid onset of analgesia is sought, administration of faster lipophilic agents, such as fentanyl via the buccal or transmucosal route, should be considered.
What is the difference between tolerance, physical dependence, addiction, and pseudoaddiction?
Tolerance is a clinical and biomolecular phenomenon characterized by diminished clinical effect after repeated exposure to a medication. Rapid escalation of doses could represent an indication of drug-aberrant behavior. Tolerance to analgesic effects of specific doses can occur later in treatment, but tolerance to side effects of opioids occurs much sooner (e.g., nausea, vomiting, sedation, constipation). Cross-tolerance refers to tolerance resulting from use of another opioid with similar pharmacologic action. Use of long-term opioids can also induce a central sensitization syndrome characterized by hyperalgesia.
Physical dependence can occur after long-term analgesia with opioids. Abrupt cessation produces a withdrawal syndrome characterized by hypertension, tachycardia, insomnia, dysphoria, hallucinations, and a subjective “craving for drug.”
In contrast, addiction is a psychobiologic syndrome associated with impaired control over substances (i.e., compulsive use despite harm or craving). Addiction appears to be influenced by genetic, social, and environmental factors and is sometimes difficult to distinguish from other forms of abuse, such as self-medication to alleviate stress, to alleviate depression, or to facilitate sleep.
A common entity, which is present in this clinical scenario, is pseudoaddiction, the “need” to increase the doses of opioids for adequate analgesia without any particular linkage to a clear addictive behavior. However, an addictive personality trait cannot be excluded.
What is preemptive analgesia; could it be considered for this patient?
The concept of preemptive analgesia was developed, although never entirely proved, approximately 20 years ago. Administration of certain medications that reduce peripheral or central nociception was associated with markedly reduced use of postoperative opioids. These medications included gabapentinoids (e.g., gabapentin, pregabalin), cyclooxygenase-2 inhibitors (e.g., celecoxib, rofecoxib), and nonsteroidal antiinflammatory drugs (NSAIDs) (e.g., ibuprofen, ketorolac).
Inhibition of prostaglandins and inflammatory cytokines in the periphery was the proposed mechanism of preemptive analgesia by NSAIDs and cyclooxygenase-2 inhibitors. Inhibition of presynaptic glutamate secretion in the substantia gelatinosa via inhibition of Ca ++ -gated channels was the proposed mechanism of gabapentinoids.
This patient would benefit from a single dose of gabapentin (600–1200 mg) given before incision and oral or intravenous (650–1000 mg) acetaminophen. Ketorolac or celecoxib used before surgical procedures with anticipated high blood volume loss poses certain challenges, such as increased intraoperative blood loss and acute kidney injury. They should be used as a last alternative after discussion with the surgeon.
What are the clinical implications of inadequate postoperative analgesia?
Inadequate postoperative analgesia can predispose patients to various complications, some with potentially ominous consequences ( Table 68-1 ). Pain increases secretion of adrenergic mediators (e.g., epinephrine, norepinephrine) from the medullo-suprarenal gland and presynaptic sympathetic afferents. Adrenergic responses cause intense vasoconstriction and sustained tachycardia, which can result in increased myocardial oxygen consumption; this may lead to cardiac dysrhythmias, coronary vasoconstriction, and poor peripheral and central perfusion. Liberation of catecholamines produces enhanced cortisol levels followed by a decreased inflammatory response through elevated cytokine and prostaglandin levels. Additionally, there is an increase in basal glucose levels with decreased pancreatic insulin secretion that ultimately leads to poor wound healing. Stress associated with inadequately treated acute pain can produce hypercoagulability and impaired activity of both innate and adaptive immunity. Consequences of these complications may include venous thromboembolic disease and increased risk of postoperative infections. Unmanaged, acute postoperative pain can delay mobilization, which can also increase the risk of venous thromboembolic disease, produce joint stiffness, delay rehabilitation, and prolong hospitalization.
|Increased adrenergic mediators||Tachycardia||Increased myocardial oxygen consumption|
|Increased cortisol levels||Decreased inflammatory response|
|Increased serum glucose||Poor wound healing|
|Hypercoagulability||Deep vein thrombosis||Risk of pulmonary embolus|
|Decreased immunity||Postoperative infections|
|Delayed mobility||Deep vein thrombosis||Risk of pulmonary embolus|
|Joint stiffness||Delayed rehabilitation|
|Respiratory splinting||Decreased tidal volume||Atelectasis|
|Pulmonary vasoconstriction||Increased dead space||Pneumonia|
|Decreased gastrointestinal motility||Increased transit time||Ileus|
|Delayed oral intake|
|Increase urinary sphincter tone||Urinary retention||Urinary tract infection|
|Increased stress and anxiety||Poor patient satisfaction|
Decreased inspiratory efforts secondary to “splinting” of the intercostal and abdominal muscles leads to a decrease in tidal volume and inspiratory reserve capacity. Pulmonary vasoconstriction results in an increase in the total pulmonary dead space. The end result is atelectasis and increased bronchial secretions predisposing these patients to tracheobronchial and pulmonary infections.
Decreased motility of the gastrointestinal tract leads to increased transit time (ileus), and the adrenergic response may lead to mucosal ischemia. Urinary retention and sphincter constriction results in inability to void, which promotes urinary tract infections.
Aside from negative impacts on various organ systems, inadequate postoperative pain control increases stress and anxiety levels in patients and families. The increased stress and anxiety levels result in overall negative experiences, which are reflected in poorer outcomes and lower pain satisfaction scores.
How is pain classified, and what is central sensitization?
Nociception is a complex process. It involves multiple mechanisms of transduction and translation of chemical reactions that occur in the periphery after injury. From there, impulses are transmitted through various channels via specific fibers and ultimately integrated at central levels (thalamus and cortex). After injury, various mediators, such as prostaglandins, cytokines, and interleukins, are liberated from activated mast cells and platelets. This group of substances, commonly known as “inflammatory soup,” generates chemical transmissions via neuronal sodium influx in dorsal root ganglia afferent fibers, comprising mostly A-delta and C fibers.
Pain is classified as either somatic, the most common cause of acute postoperative pain syndromes, or visceral, depending on its source ( Table 68-2 ). Both types of pain can be subdivided further into either neuropathic, often described as “shooting” (e.g., intercostal neuritis after thoracotomy), or nonneuropathic, which is sympathetic-mediated or non–sympathetic-mediated. Sympathetic-mediated pain can be discerned easily among other syndromes by the presence of allodynia (i.e., pain secondary to nonnoxious stimuli), hyperesthesia (i.e., increased sensitivity to nonnoxious stimuli), and hyperalgesia (i.e., increased pain secondary to noxious stimuli). This type of pain does not follow a dermatomal pattern of transmission but is intimately associated with chronic persistent postoperative pain syndrome.