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10 Articles in Volume 17, Issue #7
Abuse-Deterrent Opioids: Why Rush to Judgment?
Alcohol Screen Recommended to Reduce Opioid-Induced Respiratory Depression Overdose
Ehlers-Danlos Syndrome: An Emerging Challenge for Pain Management
Guide to Laboratory Testing in Patients With Suspected Rheumatic Disease
Letters to the Editor: Arachnoiditis, Hormone Testing, Ehlers-Danlos Syndrome
Neurocognitive Disorders: Pain Expression in the Face of Mental Deficits
Preemptive and Preventive Analgesia for Chronic Postsurgical Pain
The Effects of Religion and Spirituality on Coping Efficacy for Death and Dying
Topical Nonsteroidal Anti-inflammatory Drugs and Nephrotoxicity: Is There a Safer Option?
Transformative Care for Chronic Pain and Addiction

Preemptive and Preventive Analgesia for Chronic Postsurgical Pain

A Q&A with Lynn Cintron, MD, MS

Chronic postsurgical pain is a major clinical problem found worldwide. This pain differs in quality and location from pain experienced prior to surgery and is usually associated with neuropathic pain caused by surgical injury. To better understand the risk factors for chronic postsurgical pain and the latest clinical evidence on preemptive and preventive analgesia strategies to prevent this condition, Practical Pain Management spoke with Lynn Cintron, MD, MS, an adjunct associate clinical professor at the University of California, Irvine.

Addressing the risks associated with post-surgical pain.

How do better preemptive/preventive analgesia influence recovery and outcomes from common surgeries?

Dr. Cintron: Chronic postsurgical pain (CPSP) is a profound problem, with moderate to severe CPSP (ie, pain lasting more than 3 to 6 months after surgery) affecting up to 10% to 12% of patients undergoing common surgeries.1,2 This incidence may be underestimated because CPSP is often underdiagnosed.1 In fact, the International Association for the Study of Pain (IASP) designated 2017 as the “IASP Global Year Against Pain After Surgery.”3

There is a strong body of clinical data showing that preventive analgesia decreases pain and opioid use in acute care.4-7 Studies show other benefits, such as decreased length of hospital stay, improved function, better patient satisfaction, and improved cognitive function postoperatively.6-9

A recent study by Deng et al studied pre-emptive analgesia in the elderly, with continuous femoral nerve blocks for total knee arthroplasty.8 Results showed a decrease in visual analog scale (VAS) pain scores in recovery and decreased postoperative cognitive dysfunction.

More high-quality studies, addressing various types of surgery and different age groups, including children, are needed to see the benefit of relieving pain beyond 3 months after surgery or trauma.

How are preemptive and preventive analgesia different?

Dr. Cintron: Preemptive analgesia occurs prior to the incision of surgery or traumatic injury. Pre-emptive analgesia is ideal, but not always possible in some clinical settings (eg, traumatic injury).

Preventive analgesia is a perioperative intervention as it may occur prior to, during, and immediately after the event. While preventive analgesia can reduce acute postoperative pain, minimizing the development of chronic pain conditions can only be successful in combination with intraoperative and postoperative pain therapy, as well as social and psychological support as indicated.5

It is difficult to make definitive conclusions regarding the efficacy of preventive analgesia because data from human clinical studies on this strategy are limited. Earlier studies have been small in size, have combined multiple types of surgery, or may have studied only males and, thus, do not account accurately for the differences in pain perception between men and women. By developing large data registries, researchers will be able to make more accurate predictions on chronic and perioperative risk factors to optimize patient evaluation and treatment.

What are optimal regimens for pre-emptive/preventive analgesia? Is multimodal analgesia advised?

Dr. Cintron: Multimodal analgesia is recommended, when possible, as it has a synergistic benefit on pain relief. Animal studies have found there is a critical time frame before and immediately after nerve injury in which specific interventions can reduce the incidence of chronic neuropathic pain behaviors.4 In animal models, the following agents have demonstrated efficacy in reducing pain behaviors weeks after treatment with perineural local anesthetics, systemic intravenous local anesthetics, perineural clonidine, systemic gabapentin, tricyclic antidepressants, and minocycline. The translation of this work to humans suggests similar benefits.4

Epidurals, regional blocks, and infusions placed preoperatively appear effective at reducing nociceptive input, which can lead to central sensitization. This can reduce the likelihood of developing CPSP. Preoperative epidural infusions have been shown to reduce the use of opioids in patients and to reduce the length of stay in the recovery room.6 A retrospective review favored regional anesthesia for the prevention of chronic pain at 6 months after thoracotomy (odds ratio, 0.33) and paravertebral block for breast cancer surgery (odds ratio, 0.37) at 5 to 6 months after surgery.10

Several randomized controlled studies have demonstrated a benefit of intravenous (IV) ketamine for pain, although this depends on the type of surgery and the patient population studied. In thoracic surgery, pre-emptive IV ketamine (1.0 mg/kg) significantly decreased pain scores (P= 0.01), morphine use (P < 0.001), and C-reactive protein (P < 0.001), a sign of inflammation, in the recovery room compared with placebo.9

In a recent study of opioid-dependent patients, a complicated patient group that usually requires higher opioid doses after surgery, they received a ketamine infusion during lumbar spine surgery. Six months postoperatively, the investigators found significantly greater improvement in back pain compared to the placebo group (P = 0.005).11 Another study of opioid-dependent patients who underwent spine surgery with ketamine infusions found postoperative pain benefit at 6 weeks. Data revealed a 71% decrease in opioid use for this group, compared to placebo.12

Various clinical studies also indicate that gabapentin (600 mg) given preoperatively decreases opioid use and pain postoperatively.13 Based on various studies, Carroll et al recommended the following protocol:4,14

  • Pregabalin 300 mg orally, 2 hours prior to incision and 150 mg twice daily, following surgery for 2 weeks
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs) like venlafaxine at 37.5 mg 1 day before surgery and continued for 2 weeks postoperatively
  • Vitamin C at 500 to 1,000 mg postoperatively to decrease the incidence of complex regional pain syndrome

Recent animal investigations show that intrathecal administration of AYXI, a DNA-decoy drug candidate, in lab animals inhibits a dorsal root ganglion/dorsal 

horn transcription factor (EGR1) and limits neuronal excitability that leads to chronic pain and mechanical hypersensitivity.15

Which patients might be the best candidates for pre-emptive/preventive analgesia to prevent CPSP, and are there risk factors that must be considered?

Dr. Cintron: Most patients want preventive analgesia. However, the incidence of chronic pain appears to be greater in certain types of surgery, such as leg amputation, coronary artery bypass surgery, thoracotomy, breast surgery, inguinal hernia repair, and Cesarean section.1 Most cases of postsurgical chronic pain are neuropathic.1

A recent study showed that the incidence of chronic pain related to thoracic surgery at 6 months is 27% and that pain limited the daily activities of 8.2% of patients at that time.16 Patients with a higher severity of pain during the first 3 days after surgery showed a higher likelihood of developing chronic pain related to thoracic surgery at 6 months.16

Risk factors for developing CPSP are associated with genetic polymorphisms, psychological issues (anxiety, catastrophizing), pre-existing pain disorders (eg, fibromyalgia), prior use of high-dose opioids, severe pain immediately postoperatively, type of surgery, and female gender.17 A prospective risk factor analysis identified 5 key predictive factors: emotional overload, preoperative pain at the operative site, other chronic pain, acute postoperative pain, and comorbid stress symptoms such as tremulousness, anxiety, or disturbed sleep (Table 1).18

Are there any contraindications to pre-emptive/preventive analgesia?

Dr. Cintron: Certain interventions or medications may not be appropriate for a given patient. Attention must be paid to each patient’s needs, and anesthetic technique should be tailored to a specific type of surgery. For example, not all patients are candidates for epidurals, intrathecal injections, or paravertebral blocks (PVB) due to recent use of some blood thinners that increase the risk of epidural/spinal hematomas.

Patients with liver disease may develop liver toxicity with intravenous acetaminophen. Patients already on antidepressants or other medications, such as tramadol, could develop a serotonin syndrome if tricyclic antidepressants (eg, nortriptyline) or SNRIs (eg, duloxetine) are given. Still, there are many tools that the clinician may choose from. For example, IV ketamine may be another choice to consider when an epidural or PVB is not possible.

What role do you think genetics plays in the development of chronic pain following surgery, and how might knowing the role of genetic factors influence perioperative treatment?

Dr. Cintron: Anywhere from 20% to 60% of the variability in how people experience pain is attributable to genetic differences. Heritability accounts for many pain syndromes, such as migraines, low back pain, and carpal tunnel syndrome. Although scientists have discovered that genetics play a significant role in pain, the complexity of pain is enormous and dependent on one’s environment. Genetic researchers are not quite ready to recommend tailored pain therapies to satisfy the push for precision medicine. With some refinements, scientists believe they will find useful discoveries.19

Various genetic polymorphisms have been found in certain types of increased pain. For example, a high frequency of the HLA-DQ1 gene (human leucocyte antigen gene) is seen in patients with complex regional pain syndrome (CRPS).20 There is also ample scientific rationale to support the relationship between single nucleotide polymorphisms (SNPs) in the gene for the enzyme Catechol-O-methyltransferase (COMT) and manifestations of acute and recurrent pain.21 COMT is one of the most highly investigated genes in pain research.21 However, given the complex biology that underlies nociceptive transmission and pain manifestation, the interpretation is not straightforward.21

Still, obtaining a complete past medical and family history is very important during a preoperative evaluation to identify any red flags. In addition, a patient’s pharmacogenetics can determine what pain medications are effective in treating acute and chronic pain. Pharmacogenetics deals with individual genetic variability in drug metabolism. The polymorphic gene coding for cytochrome P450 enzyme and its subtypes differs in many people. For example, a 2D6 defect may cause codeine to be poorly metabolized to morphine and be ineffective.20

Why do you think some physicians may be against the use of pre-emptive/preventive analgesia, and what would you say to them in support of this practice?

Dr. Cintron: Part of this relates to the attitudes of physicians and their facilities. Surgeons may think these preventive strategies will increase cost and decrease efficiency, which is not necessarily so. It is far more expensive to treat chronic pain after it has progressed and centralized. Given that there is a critical window of time to intervene to reduce CPSP, physicians need to be proactive.

In my opinion, surgeons need to take a leading role in implementing preventive analgesia strategies. Some facilities are ahead of the game and have set up protocols that implement preventive analgesia, such as joint protocols.

When additional resources to run an acute pain service are lacking, anesthetists can still make an impact and prepare ahead of surgery. Surgeons can screen high-risk patients, such as those with chronic pain disorders or those taking high-dose opioids, and communicate with the anesthesia team. Furthermore, our newer health care system rates clinicians on patient satisfaction scores, which include pain management. Education is key. Not all anesthetists may be trained in regional techniques, so patients should ask ahead. Surgeons need to be educated on the benefits of preventive analgesia, especially with the increased risks associated with excess opioid use after surgery. In opioid-naive patients, many surgical procedures have been associated with an increased risk of chronic opioid use in the postoperative period, making some patients particularly vulnerable.22

Are there any other aspects of this topic that you would like to emphasize to our readers?

Dr. Cintron: Readers may refer to the IASP website (www.iasp-pain.org) for more information. It is a great resource on the topic of CPSP. It is essential for the perioperative care team to communicate early with the surgeon and identify patients who may be at greater risk for developing CPSP. This is a team effort and requires the support of the administration and operating room staff, as well as physicians and midlevel practitioners.

—Interview by Kristin Della Volpe

Last updated on: September 27, 2017
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Guide to Laboratory Testing in Patients With Suspected Rheumatic Disease

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