Chronic pain as an outcome of surgery is an area of investigation that has received increased attention over the last 15 years. Twenty years ago there were a few identified postsurgical pain syndromes, such as post-mastectomy pain syndrome and post-thoracotomy pain syndrome. The problem of persistent postsurgical pain (PPSP) as a more generalized phenomenon has received attention more recently. Cross-sectional quality-of-life surveys reveal that 40% of the population who underwent surgery in the last 3 years reported persistent pain at the surgical site. The risk for PPSP is now commonly discussed with patients before surgery. In addition to the ethical obligation to discuss this risk prospectively, there may be ways to minimize the risk for certain subpopulations of patients. In this chapter we address the extent of the problem of chronic pain following surgery in general and then, by using four specific surgeries as examples, attempt to better understand the effect of patient factors, surgical factors, and analgesic interventions on the risk for PPSP. Among the questions that we will address are the following:
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Can patients at increased risk for the development of PPSP pain be identified prospectively?
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Are there interventions that can be initiated in the preoperative, intraoperative, or immediate postoperative period to minimize the risk for chronic pain?
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What is the relative importance of patient factors, surgical factors, and analgesic factors in the development of chronic pain following surgery?
| Term | Definition |
|---|---|
| Central sensitization | Persistent postinjury changes in the central nervous system that result in pain hypersensitivity |
| Chronic pain | Pain that lasts for more than 3 mo. |
| Pain | An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage |
| Peripheral sensitization | A lowering of the threshold for a stimulus to be felt as painful |
| Preemptive analgesia | An intervention that is initiated before a nociceptive stimulus. The intervention needs to significantly decrease or eliminate the usual immediate effect of the nociceptive stimulus (e.g., pain, central sensitization) |
| Preventive analgesia | An intervention that is initiated before a nociceptive stimulus (e.g., surgical incision), and then intervention is continued until the major nociceptive stimulus has abated |
Pain is a common phenomenon after surgery. Some degree of postsurgical pain is expected after most surgical procedures. However, the extent of acute postoperative pain is highly variable among individuals undergoing similar surgery. As a generalization, more extensive surgical procedures are associated with greater acute pain. In many studies the extent of acute postoperative pain has been a predictor of PPSP. Consequently, a number of studies have been conducted to address questions that may relate to both acute postoperative pain and PPSP. Does the use of minimally invasive approaches have advantages beyond the acute postoperative period? Does our ability to alter the acute pain experience influence the probability of PPSP? If acute postoperative pain control alters PPSP, how does that happen? What patient factors are predictive of PPSP? We will explore these questions by using the examples of breast surgery, hip surgery, inguinal hernia repair, and thoracotomy.
In a recent review, Katz and colleagues emphasized that the timing of the preemptive intervention needs to correlate with the period of intense nociceptive stimulation and not just be a single intervention of short duration. They suggested that the term “preventive analgesia” would be more useful, and we agree, although it has been pointed out that evidence to support the concept of preventive analgesia is weak. The concept of preemptive analgesia originated with a paper by Clifford Woolf in 1983. The findings of this study, when combined with what is known as wind-up, or increasing pain intensity when a given painful stimulus is delivered repeatedly above a critical frequency, gave rise to the hope that interventions that decrease nociceptive input or block central sensitization would have lasting analgesic benefit. How pain progresses from acute nociceptive pain, to subacute pain, to chronic pain has been reviewed by Devor and Seltzer, who incorporated animal model data and human data. Briefly, persistent acute nociceptive stimulation elicits both pain and activation of sensitization in the spinal cord. In the subacute pain period there is probably some nociceptive stimulation that can maintain the sensitization and pain. In some models and some individuals there does not appear to be any resolution of this sensitization. It is not clear whether some nociceptive input is needed to maintain the sensitization or whether changes in the spinal cord following nerve injury are sufficient to maintain sensitization and thus pain.
Factors Influencing the Development of Persistent Postsurgical Pain
Numerous factors related to the surgery appear to be of importance. First among these is the surgical procedure. Previous reviews have documented that the prevalence of chronic pain varies with the type of surgery, with some surgical procedures such as lower extremity amputation and posterolateral thoracotomy having a high prevalence of chronic pain (greater than 50%). Table 19.2 summarizes the prevalence of chronic pain following many common surgical procedures. As shown in this table, chronic pain is infrequent following some surgical procedures, such as cataract extraction, but prevalent following other surgical procedures, such as thoracotomy. Additionally, the prevalence of pain may decrease following certain surgeries (hip arthroplasty, lumbar laminectomy for a herniated disk) but increase following other surgeries (thoracotomy, breast surgery). This does not mean that PPSP cannot result from a surgery such as hip arthroplasty, but rather that the majority of patients experience a reduction in pain following the procedure, and a smaller number may have increased pain.
| Surgical Procedure | Prevalence of Chronic Pain | Prevalence of Preoperative Pain |
|---|---|---|
| Amputation, lower extremity | Phantom pain, 70% Stump pain, 62% | Very common, chronic, continuous ischemic pain |
| Arthroplasty, hip | 27% | Common, chronic, incident arthritic pain |
| Arthroplasty, knee | 44% | Common, chronic, incident arthritic pain |
| Cataract with lens implant | <1% | Infrequent |
| Cesarean section | 6% | Common, intermittent, acute labor pain |
| Cholecystectomy | 23% | Common, variable, from acute cholecystitis to chronic vague abdominal pain |
| Colectomy | 28% | Uncommon |
| Dental, root canal | 12% | Common, usually with breakage or infection |
| Hernia repair, inguinal | 12% | Common, incident pain with peritoneal stretch |
| Lumbar spine surgery for herniated disk | 44% | Very common, primary reason for surgery |
| Mammoplasty, augmentation | 20% | Infrequent |
| Mastectomy plus axillary dissection | 30% 50% | Infrequent |
| Prostatectomy, radical | 32% | Infrequent |
| Sternotomy | ||
| CABG | 30% | Common, intermittent, exertional angina |
| Valve | 32% | Infrequent |
| Thoracotomy | ||
| Posterolateral | 50% | Infrequent |
| VATS | 31% | |
| Vasectomy | 20% | Rare |
Within a given type of operation, a number of surgical approaches may be possible. For thoracotomy, an anterior approach appears to be associated with less acute and chronic pain than the classic posterolateral approach. Additionally, there may be less acute and chronic pain with visually aided thoracoscopic surgery than with the same operation performed as an open procedure. Likewise, laparoscopic inguinal hernia repair is associated with less acute pain and less chronic pain than open inguinal hernia repair is. Thus there are data to support the hypothesis that minimally invasive surgical procedures are associated with less chronic pain than the same operations performed as open procedures.
Another factor may be what has been referred to as “volume-dependent outcome.” Database studies demonstrate that for a number of major high-risk surgeries, outcome is worse when the procedure is performed in a low-volume institution and that a large part of the risk can be attributed to low-volume surgeons. We previously noted that in the case of hernia repair, the lowest prevalence of chronic pain is reported by high-volume hernia centers. The incidence of complications, including chronic pain, following laparoscopic hernia repair has been noted to be greater early in the experience of surgeons. This may be analogous to the observation that hernia surgery performed by trainees has a higher incidence of recurrence and chronic pain than the same surgery performed by experienced surgeons.
Adjuvant treatments associated with a number of surgical procedures for cancer may also play a role in the development of PPSP. In particular, radiation therapy for women undergoing breast and axillary surgery is associated with an increased probability of chronic pain. Whether adjuvant therapies in the perioperative period affect the risk for chronic postsurgical pain after other cancer surgeries has not yet been determined.
It should be understood that patients vary in their sensitivity to pain and in other factors that may predict the evolution of acute pain to chronic pain. This has been an area of research for many years, with Lasagna and Beecher finding that one third of patients following surgery did not experience significant pain relief with commonly used dosages of morphine. Likewise, in subsequent studies, Lasagna and associates continued to find significant patient variability in response to both surgery and opioids and that patients’ reports of pain sensitivity predicted neither the extent of pain nor the response to opioids. A number of more recent studies have investigated the genetic basis of pain variability (see Young and colleagues for a review ).
There are also psychological factors, other than pain sensitivity, that appear to predispose certain individuals to experiencing pain. Psychological vulnerability has been found to be a predictor of long-term pain and symptoms following cholecystectomy. Gatchel and coworkers noted a set of psychosocial risk factors for acute back pain to evolve into chronic back pain. It appears that the strongest predictors involve deficits in coping ability, neuroticism, and somatization, although depression and anxiety add a component. Catastrophizing may also be a predictor of PPSP.
The intensity of pain in the postoperative period has been a reproducible predictor of chronic pain following a number of surgeries, including lower extremity amputation, thoracotomy, mastectomy, cholecystectomy, and inguinal hernia surgery. Usually, pain intensity is measured directly with some instrument, but analgesic consumption is also frequently measured as a surrogate algometer. When looking at studies of interventions aimed at decreasing the intensity of acute pain and reducing the prevalence or intensity of chronic pain, there are a number of factors that we believe should be considered.
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What intervention or interventions were implemented?
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When were they initiated relative to the initial nociceptive stimulus?
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How long were the interventions continued?
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Were the interventions effective in decreasing acute pain or acute opioid consumption?
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Were the doses of medication used in a clinically reasonable range?
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Was there a systematic evaluation of pain and symptoms both acutely and chronically?
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What chronic pain was assessed?
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Were the randomization and blinding adequate to eliminate investigator bias?
We will be reviewing studies for some selected surgical procedures in the following sections and will try to identify how some of these factors may have influenced the observed outcome. In particular, specific drugs such as gabapentin or pregabalin have been advocated to decrease the prevalence of PPSP, but the results have been highly variable.
Breast Surgery
The majority of studies of chronic pain following breast surgery involve women with cancer. There are also some reports of reasonable quality following augmentation mammoplasty or reduction mammoplasty. Studies of both cancer surgery and augmentation mammoplasty document a significant prevalence of chronic pain following breast surgery (see Table 19.2 ). Women undergoing cancer surgery also have problems with persistent arm pain following axillary dissection. Radiation therapy and chemotherapy following breast surgery will further increase the prevalence of persistent pain. Careful handling of the intercostal brachial nerves in the axilla appears to decrease the risk for persistent pain. A number of studies now demonstrate that axillary sentinel node biopsy is associated with less persistent pain than primary axillary dissection is. Table 19.3 presents the risk (odds ratio) for persistent pain when sentinel node biopsy is compared with axillary dissection. In women with negative pathology on a sentinel node biopsy, arm pain and other arm symptoms are significantly less likely to develop. In women who underwent secondary axillary node dissection, chronic pain was as likely or more likely to develop than in those who underwent primary axillary node dissection.
| Experimental Group | Control Group | Odds Ratio | 95% Confidence Interval | Study Type | N | Follow-up (mo) | Reference |
|---|---|---|---|---|---|---|---|
| Sentinel node biopsy | Axillary dissection | 0.42 | 0.34-0.51 | RCT | 2573 | 12-24 | Veronesi, Purushotham, Fleissig, Del Bianco, Lucci, Fougo |
| Paravertebral block | General anesthesia | 0.10 | 0.04-0.27 | RCT | 118 | 3-6 | Kairaluoma, Iohom, Ibarra |
| Gabapentin | Control | 0.52 | 0.28-0.94 | RCT | 191 | 3-6 | Fassoulaki, Fassoulaki, Amr |
Breast-conserving surgery has been associated with a higher prevalence of chronic pain than simple mastectomy, but only in studies where persistent pain was assessed as a tertiary, not a primary or secondary, outcome, and this association has not been found consistently. There are no randomized studies on this issue.
Paravertebral block has been advocated as an analgesic technique for breast surgery and the immediate postoperative period. In 2006 two randomized controlled studies looked at the influence of perioperative paravertebral blockade on persistent pain following breast surgery. Both found a significantly lower prevalence of chronic pain in women who had the block. One was a follow-up study of 60 women who had participated in an acute perioperative pain study. In this study, the prevalence of pain at both 6 and 12 months was significantly lower in the women who had received a block (17% vs. 40% at 6 months and 7% vs. 33% at 12 months). The second study was smaller (29 subjects) and involved placement of a paravertebral catheter preoperatively in patients in the treatment arm. A dose of 10 mL of 0.25% bupivacaine was administered before surgery and every 12 hours for 48 hours. A telephone follow-up inquired about pain 3 months following surgery (“Do you have chronic pain as a result of your breast surgery?”). The paravertebral block group had a significantly lower prevalence of pain at 3 months (0% vs. 80%). There has now been a third study published supporting the use of paravertebral block to decrease the prevalence of PPSP at 4 to 5 months. If the data from these three studies are combined, the calculated odds ratio of preventing PPSP with a paravertebral block is highly significant (see Table 19.3 ).
A number of randomized controlled studies have investigated perioperative interventions to decrease the prevalence of persistent pain after breast surgery. Romundstad and associates compared a single dose of methylprednisolone (125 mg) with a single dose of parecoxib (40 mg) and placebo in women undergoing augmentation mammoplasty. At 12 months the prevalence of pain at rest in the three groups was 16%, 7%, and 16%, respectively. Evoked pain was found in 16%, 14%, and 29%, respectively. The calculated odds ratio and 95% confidence intervals were 0.49 (0.30 to 0.74) for methylprednisolone versus placebo and 0.40 (0.25 to 0.64) for parecoxib. Fassoulaki and colleagues published two randomized controlled studies of perioperative gabapentin. In the first, women received gabapentin, 400 mg three times a day starting the evening before surgery, or mexiletine, 200 mg three times per day, or placebo three times per day. There were no significant differences in pain prevalence or intensity or in analgesic requirement at 3 months, although the character of the pain in the control group tended to be burning rather than throbbing, aching, or stabbing. In the second study, women undergoing breast cancer surgery received a combination of gabapentin, 400 mg four times a day for 10 days starting the evening before surgery, plus EMLA cream (20 g) for 3 days starting the day of surgery, plus intraoperative irrigation of the brachial plexus with 10 mL of 0.75% ropivacaine. The control group underwent placebo administration in each of the interventions. This study found a significantly decreased prevalence of pain at both the 3- and 6-month follow-up in the intervention group (30% vs. 57% at 6 months). The calculated odds ratio for pain at 6 months was 0.32 (0.18 to 0.62). Amr and Yousef randomized patients scheduled for mastectomy plus axillary dissection to receive gabapentin, 300 mg/day, or venlafaxine, 37.5 mg/day, or control (all for 10 days starting the day before surgery). At 6 months’ follow-up, pain scores with movement were lower in the venlafaxine group than in the gabapentin or control groups. It is not clear, however, whether gabapentin can reliably alter long-term pain following breast surgery. If the three gabapentin studies are combined (see Table 19.3 ), there appears to be a benefit, but the dose and duration required to achieve maximal benefit need further investigation, and follow-up at 12 months and longer is needed.
Clearly, there is a need for follow-up studies to confirm these findings on perioperative interventions aimed at reducing persistent pain after breast surgery, but early results suggest utility for these interventions.
Breast Surgery
The majority of studies of chronic pain following breast surgery involve women with cancer. There are also some reports of reasonable quality following augmentation mammoplasty or reduction mammoplasty. Studies of both cancer surgery and augmentation mammoplasty document a significant prevalence of chronic pain following breast surgery (see Table 19.2 ). Women undergoing cancer surgery also have problems with persistent arm pain following axillary dissection. Radiation therapy and chemotherapy following breast surgery will further increase the prevalence of persistent pain. Careful handling of the intercostal brachial nerves in the axilla appears to decrease the risk for persistent pain. A number of studies now demonstrate that axillary sentinel node biopsy is associated with less persistent pain than primary axillary dissection is. Table 19.3 presents the risk (odds ratio) for persistent pain when sentinel node biopsy is compared with axillary dissection. In women with negative pathology on a sentinel node biopsy, arm pain and other arm symptoms are significantly less likely to develop. In women who underwent secondary axillary node dissection, chronic pain was as likely or more likely to develop than in those who underwent primary axillary node dissection.
| Experimental Group | Control Group | Odds Ratio | 95% Confidence Interval | Study Type | N | Follow-up (mo) | Reference |
|---|---|---|---|---|---|---|---|
| Sentinel node biopsy | Axillary dissection | 0.42 | 0.34-0.51 | RCT | 2573 | 12-24 | Veronesi, Purushotham, Fleissig, Del Bianco, Lucci, Fougo |
| Paravertebral block | General anesthesia | 0.10 | 0.04-0.27 | RCT | 118 | 3-6 | Kairaluoma, Iohom, Ibarra |
| Gabapentin | Control | 0.52 | 0.28-0.94 | RCT | 191 | 3-6 | Fassoulaki, Fassoulaki, Amr |
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