The Role of Intra-Operative Nerve Injury in Persistent Postoperative Pain

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INTRODUCTION

Surgical procedures invariably results in tissue trauma including injury to cutaneous and deep tissue sensory nerve fibres, suggesting that intraoperative nerve injury is a key factor when investigating the pathogenetic factor in persistent postoperative pain. Surgical pain models such as inguinal herniotomy, thoracotomy and mastectomy, allows for detailed studies of the relative role of nerve injury in the development of persistent postsurgical pain together with other potential predisposing factors such as gender, age, genetics, and psycho-social variables [25,26], which can be assessed before injury, as opposed to other chronic pain condition such as low-back pain, headache, etc. Understanding the role of nerve injury and separating it from other causes of PPSP, is essential for future advances in treatment and preventive strategies, and the findings may be expanded into the understanding of other non-surgical pain syndromes as well. This chapter will focus on the current knowledge mainly from three major surgical procedures (mastectomy, herniotomy and thoracotomy) and discuss the need for further studies, especially the role of cutaneous vs. deep nerve injury and hyperalgesia in the development and maintenance of persistent postoperative pain.

THE CASE OF INGUINAL HERNIOTOMY

Inguinal herniotomy has been thoroughly studied as a model for persistent postoperative pain, and especially for the role of intraoperative nerve injury, as three to four nerves transverse the surgical field in groin hernia surgery, depending on the surgical approach. Thus, in open repair the ilioinguinal, iliohypogastric and genitofemoral nerve, and in laparoscopic, also the lateral femoral cutaneous nerve are at risk for intra-operative nerve damage. Furthermore, herniotomy is performed in large numbers of patients by standardized procedures, has low occurrence of psycho-pathology and no exposure to radio or chemotherapy which is a well-documented risk factor for sensory disturbances and pain, making it a potential ideal model for the study of nerve damage as a risk factor for persistent postoperative pain.

Preoperative Sensory Function

Before postoperative neuropathy is assumed to have a causal relationship to intraoperative nerve injury it is critical to assess the preoperative sensory function. In groin herniotomy, preoperative hernia pain has been shown to be related to development of persistent pain [3,34], which may suggest that pre-operative hernia pain induces nociceptive neuroplastic changes that facilitate nociceptive signaling to the central nervous system (CNS) and ultimately lead to continuation of pain after surgery. Pre-operative neuroplastic changes are reported in other visceral pain syndromes (gallstone and appendicitis) [17,44,45], where sensory changes such as hyperalgesia in the painful or referred area are related to pain intensity. Thus, the preoperative peripheral sensory function in groin hernia patients could potentially be affected by the hernia, either due to the physical protrusion causing stretching of the tissue or more likely from nociceptive induced neuroplasticity.

However, in a study of 41 patients scheduled for herniotomy where sensory function was assessed by a standardized QST protocol [4], no correlation between any test result and level of pain on the hernia side was found, and sensory function was not significantly different between the two groins.

In a larger study (n = 442) testing the warmth and heat pain detection thresholds (WDT and HPT) and response to a tonic 47^oC heat stimulation on the arm and groin, preoperative pain was also not associated with alterations in local preoperative nociceptive function in the groin. The finding that the sensory function in the groin and arm were closely related also supports that the preoperative groin hernia pain does not cause general hyperalgesia [3].

Thus, assessment of preoperative sensory function has not revealed signs of pain induced neuroplasticity in groin hernia patients or other changes when compared to the naïve side. In this sense, hernia patients do not exhibit the hyperalgesia seen in other pain syndromes (gallstone, migraine, appendicitis) [29,44,45,52]. These findings advocate assessment of pre-operative sensory in other surgical procedures before sensory changes in persistent postsurgical pain patients can be contributed to intra-operative nerve damage.

Acute Sensory Dysfunction and Development of Persistent Postoperative Pain

Acute postoperative pain is correlated to and predicts persistent postoperative pain [2,25,26]. The causal relationship whether acute pain causes persistent pain or if both acute and persistent pain are caused by the same pre- and intraoperative factors are not yet clear. Information on acute postoperative sensory function would benefit our understanding of why acute pain predicts persistent pain and if it could be due to nociceptive plasticity. In a 20 patients pilot study of the role of DNIC on acute and postoperative pain and hyperalgesia after abdominal surgery, acute postsurgical pressure hyperalgesia was seen more often in patients who later reported pain at 6 months and at that time also had pressure hyperalgesia [54]. However, the data are not clear as hyperalgesia was seen more often in the pain-free group at 3 months, and the surgical group consisted of various upper and lower abdominal and urogenital surgical procedures, making the findings intriguing, but inconclusive. Only a small study has assessed sensory function between the operated and contralateral side by QST before groin herniotomy, one week after and 2 ½ years postoperatively, where acute thermal and mechanical hypoesthesia and pressure hyperalgesia were found on the operated side, but no relationship between acute pressure hyperalgesia and persistent pain were seen after 2 ½ years [5], but the limited number of patients hinders firm conclusions.

Thus, inguinal herniotomy results in acute cutaneous hypoesthesia and deep hyperalgesia, but the data on the effect on persistent pain is sparse, calling for further larger studies.

Late Sensory Function and Pain – Pain-Free Patients

One of the main advantages of investigating postoperative pain, is the availability of an optimal control group of pain-free patients treated for the same illness with the same procedure as those who develop pain. As opposed to comparing pain patients to healthy volunteers, the pain-free control group allows for understanding the specific role of nerve injury (i.e. sensory dysfunction), while controlling for other potential factors [26].

Several studies using questionnaires and bedside sensory testing to describe the relationship between pain and sensory dysfunction after groin herniotomy, show a clear trend of sensory disturbances (numbness, paresthesia, foreign body sensations etc.) occurring in 40–50% of pain patients, but also in 10–40% of pain-free patients [15,32,38]. More details on the characteristics of sensory function in pain free patients come from a study of 40 pain free-patients operated two years before QST [7]. Sensory mapping on the operated side showed 52% of patients had areas of cold hypoesthesia, 40% brush hypoesthesia, 35% pinprick hypoesthesia, and 5% pinprick hyperalgesia. When the two sides were compared, QST revealed hypoesthesia and hypoalgesia to cold, warmth, heat and tactile stimulation were found on the operated, but pain-free, side. Pressure and pressure tolerance thresholds were significantly lower (hyperalgesia) on the operated side compared to the contralateral.

Pain thresholds on both sides were significantly correlated suggesting that the clinically irrelevant cutaneous hypoalgesia and deep hyperalgesia found in pain-free operated patients may sensitize contralateral neurons on a central nervous level (a so-called mirror-effect), similar to what is seen other nerve injuries [35,37]. However, there is little if no indication of central/peripheral nociceptive hyperexitability in pain-free operated patients as evidenced by the finding that although repetitive stimulation with a von Frey fiber elicited pain in 15% of patients, pain ceased when stimulation stopped in all patients, and without after-sensations.

These findings show that hernia surgery leads to cutaneous hypoesthesia and hypoalgesia, and deep tissue hyperalgesia in pain-free patients. These findings are similar to those reported from other surgical models, including thoracotomy [55] mastectomy [18,49] and traumatic peripheral nerve injury after various surgical procedures [30].

The reason why these patients do not experience pain despite having reduced pain thresholds is not clarified, but may be that a relevant pain stimulus like the pressure algometry does not occur in everyday life, or that these patients have a better inhibitory pain modulation than pain patients [46]. However, the findings from the operated side clearly show that a pain-free operated control group is essential when sensory findings in persistent postoperative pain, are interpreted to evaluate the role of intraoperative nerve-injury. Assessment of sensory function should thus, not only compare side to side differences, adjusting for mirror-effects or generalized sensitization, but also perform individual characterization based upon normative data from the pain-free operated patients, and that reference data from an unoperated side should be used with caution.

Late Sensory Function and Pain – Pain Patients

When postherniotomy pain patients are compared to a pain-free operated control group, they do not only have a higher incidence of sensory disturbances [1,33], assessed by sensory mapping, but also more severe disturbances and includes positive phenomena such as hyperalgesia and temporal summation wind-up like pain [24,33]. The first QST study involved a combination of 20 persistent pain patients and 52 pain-free operated patients [33] with a 6–12 months follow-up. Hypoesthesia and allodynia were seen significantly more often in pain patients, but pressure pain thresholds and cutaneous thresholds were not significantly different between the two groups, which may be explained by the fact that pain-patients only had mild pain (median VAS 22, range 12–30), thereby not including those patients that may have more severe nerve damage and/or nociceptive sensitization.

Later, and larger, detailed QST studies comparing patients with moderate/severe persistent postherniotomy pain have revealed significant lower mechanical and pressure pain thresholds (hyperalgesia) and significantly increased thermal thresholds (hypoesthesia/-algesia) in pain patients when compared to values from pain-free patients [1,2]. Further support for nerve injury as a characteristic feature in postherniotomy pain, comes from a large-scale prospective study with QST in all 442 patients [3

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