Factors affecting recurrence of pain after surgery for chronic pancreatitis: A retrospective and prospective study

Abstract

Backgrounds/Aims

Postoperative pain recurrence is a challenging issue in chronic pancreatitis (CP). This study explores the incidence and factors contributing to recurrent pain after surgery.

Methods

An ambispective observational study evaluated patients with painful CP undergoing surgery from 2011 to 2022. The intensity frequency consequence (IFC) pain score and the painDETECT questionnaire were utilized to assess pain before and after surgery. Patients were categorized into 2 groups based on their IFC pain scores: a pain group and a pain-free group. Clinical, radiological, surgical, and post-surgical parameters were compared between these groups using the student t-test and logistic regression for continuous and categorical variables, respectively. A p-value of < 0.05 was deemed significant. Multivariate analysis was conducted.

Results

A total of 125 patients were enrolled (pain group, 71 [56.8%]; pain-free group, 54 [43.2%]). In the pain group, 65 experienced mild and 6 experienced moderate pain. The average post-surgery pain score was significantly lower than the pre-surgery score (13.7 vs 2.5, p < 0.001). Multivariate analyses revealed that intravenous (IV) analgesics and preoperative endoscopic interventions were independent predictors of recurrent pain.

Conclusions

The incidence of recurrent pain in CP patients post-surgery was 56.8%, with a significant reduction in pain intensity postoperatively. Patients who required preoperative IV analgesics and underwent endoscopic interventions demonstrated a higher risk of recurrent pain. Neuropathic pain was not identified as a cause of pain recurrence in this study.

INTRODUCTION

In patients with chronic pancreatitis (CP), pancreatic pain is the most prevalent and debilitating symptom. It often leads to opioid dependency, dietary and lifestyle restrictions, frequent hospital visits, work absenteeism, and unemployment [1].

In current practice, initial pain management is medical, involving therapies from uncoated pancreatic enzymes and antioxidants to non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Endoscopic intervention usually follows as the next step. Surgery is a pivotal option in pain management, albeit typically the final step in the therapeutic hierarchy [2].

Indications for surgery in CP include intractable pain (most common), symptomatic local complications (such as bile duct stenosis, duodenal stenosis, pseudocyst), unsuccessful endoscopic management, and suspicion of malignancy [3-6].

Recurrent pain after surgery is an important problem, however, only a few studies address the long-term outcomes of pain control using validated scoring systems, with the incidence of recurrent pain ranging from 43% to 52% in these studies. Several factors contribute to recurrent pain after surgery [7,8]. Identifying the factors that influence the recurrence of pain after surgery in CP is pivotal for enhancing patient selection, optimizing surgical methods, and improving postoperative outcomes. While prior research has addressed surgical results in CP, the focus has predominantly been on short-term pain alleviation and procedural efficacy, rather than the long-term recurrence of pain and its determinants. This study seeks to fill this gap by pinpointing the primary factors that contribute to the recurrence of pain following surgical intervention in CP. The goal of this study is to document the incidence of and identify the factors responsible for the recurrence of post-surgery abdominal pain, utilizing a validated scoring system, in patients with CP undergoing a drainage procedure.

MATERIALS AND METHODS

This study is an ambispective observational study carried out from January 2011 to May 2022, following approval from the institute ethics committee (2023-92-MCh-EXP-52 PGI/BE/206/2023). All patients between 14–75 years of age who were admitted with CP and underwent a drainage procedure at the Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute, Lucknow were included in the study after obtaining informed consent from the patient. The study excluded patients not eligible for at least 6 months of follow-up and those in whom pain evaluation was difficult due to severe associated comorbid illnesses or social reasons.

The diagnosis was established based on clinical symptoms and morphological alterations observed in imaging studies. A pancreatic duct diameter of 7 mm or more was considered dilated according to the Marseilles criteria [9]. Pain that persisted or reemerged 6 months following surgery was defined as recurrent pain for the purposes of this study.

The primary indications for surgery among these patients were intractable pain or unsuccessful endoscopic interventions. The choice of surgical approach was informed by the morphology of the pancreatic duct, enlargement of the pancreatic head, and locoregional complications.

Frey’s procedure was performed on patients exhibiting inflammatory enlargement of the pancreatic head with no suspicion of malignancy. Longitudinal pancreatojejunostomy (LPJ) was executed in patients without pancreatic head enlargement but with a dilated pancreatic duct. The presence of pseudocysts did not influence the chosen surgical methodology. Concurrent surgical biliary drainage in the form of side-to-side choledochojejunostomy was indicated for patients with choledocholithiasis or a symptomatic bile duct stricture. Splenectomy was conducted in cases of splenic vein thrombosis associated with sinistral portal hypertension or a splenic artery aneurysm.

The IFC (intensity frequency consequence) pain score [10] and the painDETECT questionnaire [11] were utilized to evaluate pain severity and neuropathic pain presence, respectively. The IFC score comprises intensity (I), frequency (F), and consequences (C), with each component receiving a score from 0 to 8. The total score ranges from 0 to 24, with higher scores indicating severe pain. Based on the overall IFC score, patients were categorized into mild (scores 1–8), moderate (scores 9–14), or severe (scores 15–24) pain groups. The painDETECT questionnaire, consisting of 9 items, included 7 weighted sensory descriptor items ranging from ‘never’ to ‘very strongly,’ and 2 items reflecting the spatial (radiating) and temporal characteristics of the individual pain pattern [11].

For all patients, both the IFC and painDETECT scores were documented before surgery and at the last follow-up, which occurred at least 6 months postoperatively. Patients were classified based on the overall IFC score into a pain group and a pain-free group, to identify factors associated with the recurrence of pain.

Continuous data were presented as means and were compared between groups using the student’s t-test. Categorical variables were analyzed using a logistic regression model. Only variables with p < 0.05 in the univariate analysis were included in the multivariate logistic regression model. p ≤ 0.05 was considered statistically significant. All reported p values were two tailed. Statistical analysis was performed using SPSS version 26.0 (IBM Corp.).

RESULTS

During the study period, among the 125 patients who underwent a drainage procedure for CP, the male-to-female ratio was 58:67, with a mean age of 32.6 ± 9.3 years (range 16–65 years) (Table 1, 2). LPJ was performed in 53 patients (42.4%) and 72 patients (57.6%) underwent Frey’s procedure. The etiology included alcohol in 18 patients (14.4%), pancreas divisum in one (0.8%), and was idiopathic in the remaining 106 (84.8%). The majority of patients suffered from moderate to severe pancreatic pain, which was intermittent in 64 (51.2%) and continuous in 61 (48.8%). The average duration from the onset of symptoms to surgical referral was 48.6 ± 44.0 months (range 2–192 months). Preoperative endoscopic therapy was performed in 46 patients (36.8%).

Table 1.

Univariate analysis of demographic and clinical factors affecting recurrence of pain after surgery for chronic pancreatitis

Parameter	Overall (n = 125)	Pain group (n = 71)	Pain-free group (n = 54)	Univariate analysis (p)
Average age at diagnosis (yr)	32.6 ± 9.3	33.5 ± 9.12	31.35 ± 9.5	0.19
Symptom duration (mon)	48.6 ± 44.0	45.8 ± 45.45	52.26 ± 44.24	0.43
Sex				0.28
Male	58 (46.4)	30 (42.3)	28 (51.9)
Female	67 (53.6)	41 (57.7)	26 (48.1)
Pain type				0.10
Continuous	61 (48.8)	30 (42.3)	31 (57.4)
Intermittent episodic	64 (51.2)	41 (57.7)	23 (42.6)
Pain severity
Mild	4 (3.2)	2 (2.8)	2 (3.7)	0.39
Moderate	59 (47.2)	30 (42.3)	29 (53.7)	0.78
Severe	62 (49.6)	39 (54.9)	23 (42.6)	0.20
Preoperative intravenous analgesic medication use	67 (53.6)	44 (62.0)	23 (42.6)	0.03
Alcohol consumption	18 (14.4)	12 (16.9)	6 (11.1)	0.36
Preoperative DM	33 (26.4)	19 (26.8)	14 (25.9)	0.91
Preoperative steatorrhea	40 (32.0)	24 (33.8)	16 (29.6)	0.62
Weight loss	40 (32.0)	19 (26.8)	21 (38.9)	0.15
Jaundice	12 (9.6)	9 (12.7)	3 (5.6)	0.19
Imaging CBD
Undilated	96 (76.8)	51 (71.8)	45 (83.3)	0.54
Dilated	26 (20.8)	17 (23.9)	9 (16.7)	0.99
Stricture	3 (2.4)	3 (4.2)	0 (0)	0.99
Imaging pancreas atrophy	117 (93.6)	67 (94.4)	50 (92.6)	0.68
Imaging pancreatic duct calcification	123 (98.4)	69 (97.2)	54 (100)	0.99
Imaging parenchymal calcification	83 (66.4)	45 (63.4)	38 (70.4)	0.41
Imaging MPD
Undilated	3 (2.4)	2 (2.8)	1 (1.9)	0.11
Dilated	103 (82.4)	54 (76.1)	49 (90.7)	0.53
Stricture	19 (15.2)	15 (21.1)	4 (7.4)	0.29
Pseudocyst on Imaging	20 (16.0)	12 (16.9)	8 (14.8)	0.75
Endoscopic intervention	46 (36.8)	32 (45.1)	14 (25.9)	0.03
Surgery				0.74
Frey’s	72 (57.6)	40 (56.3)	32 (59.3)
LPJ	53 (42.4)	31 (43.7)	22 (40.7)
MPD stricture at surgery	45 (36.0)	29 (40.8)	16 (29.6)	0.19
Pancreas texture				0.20
Firm	85 (68.0)	45 (63.4)	40 (74.1)
Hard	45 (36.0)	26 (36.6)	14 (25.9)
MPD calculi at surgery
No stone in MPD	8 (6.4)	6 (8.5)	2 (3.7)	0.75
Head & uncinate	93 (74.4)	52 (73.2)	41 (75.9)	0.28
Head and body	7 (5.6)	4 (5.6)	3 (5.6)	0.73
Head, body and tail	17 (13.6)	9 (12.7)	8 (14.8)	0.98
Pseudocyst at surgery	15 (12.0)	9 (12.7)	6 (11.1)	0.79

Values are presented as mean ± standard deviation or number (%).

DM, diabetes mellitus; CBD, common bile duct; MPD, main pancreatic duct; LPJ, lateral pancreaticojejunostomy.

Table 2.

Univariate analysis of postoperative factors affecting recurrence of pain after surgery for chronic pancreatitis

Parameter	Overall (n = 125)	Pain group (n = 71)	Pain-free group (n = 54)	Univariate analysis (p)
Length of postoperative stay (day)	9.9 ± 6.2	9.9 ± 5.54	9.96 ± 7.19	0.95
Postoperative SSI	24 (19.2)	17 (23.9)	7 (13.0)	0.12
Postoperative PJ leak	19 (15.2)	8 (11.3)	11 (20.4)	0.16
Intra-abdominal collection	13 (10.4)	5 (7.0)	8 (14.8)	0.16
Postoperative bleeding	6 (4.8)	3 (4.2)	3 (5.6)	0.73
SAIO	4 (3.2)	3 (4.2)	1 (1.9)	0.46
DGE	3 (2.4)	2 (2.8)	1 (1.9)	0.72

Values are presented as mean ± standard deviation or number (%).

SSI, surgical site infection; PJ, pancreaticojejunostomy; SAIO, subacute intestinal obstruction; DGE, delayed gastric emptying.

Symptomatic biliary obstruction occurred in 12 (9.6%) patients, and pseudocyst was present in 15 (12.0%) patients.

After a median follow-up of 35 months, the mean postoperative IFC pain score (2.5 ± 2.8) was significantly lower than the preoperative score (13.7 ± 3.3) (p < 0.01) (Table 3). At follow-up, complete pain relief was achieved by 54 patients, 65 experienced mild pain, and the remaining 6 had moderate pain. Prior to surgery, 67 patients (53.6%) required intravenous (IV) analgesics for pain management, while 58 patients (46.4%) used oral NSAID/opiate analgesics. Postoperatively, only 36 patients required oral NSAID/opiate analgesics, and none required IV analgesics. A preoperative assessment indicated predicted neuropathic pain in 6 patients. Nevertheless, the painDETECT questionnaire did not identify neuropathic pain in any of these patients with recurrent pain post-surgery.

Table 3.

Comparison of pain scores pre and postoperatively

Parameter	Overall	Pain group (n = 71)	Pain-free group (n = 54)
IFC preoperative pain score	13.7 ± 3.3	14.8 ± 3.14	12.3 ± 2.98
IFC postoperative pain score	2.5 ± 2.8	4.4 ± 2.43	0
painDETECT preoperative pain score	5.84 ± 4.04	6.3 ± 4.60	5.17 ± 3.08
painDETECT postoperative pain score	0.91 ± 2.04	1.3 ± 2.22	0.37 ± 1.62

IFC, intensity frequency consequence.

As shown in Table 2, 24 (19.2%) patients had wound infections, 13 (10.4%) developed intra-abdominal collections, 19 (15.2%) suffered from pancreatic fistulas, 6 (4.8%) experienced intra-abdominal bleeding, 3 (2.4%) had delayed gastric emptying, and 4 (3.2%) faced postoperative subacute intestinal obstruction. Among these, 4 patients required re-exploration (2 for fistulas, 2 for bleeding). All patients recovered. No mortality was reported in our study.

Multivariate analysis predicting post-surgical recurrence of pain showed that the pain group (n = 71) significantly differed from the pain-free group (n = 54) in terms of preoperative endoscopic interventions (32 vs 14, p = 0.030) and the need for preoperative IV analgesics (44 vs 23, p = 0.033) (Table 4).

Table 4.

Multivariate analysis of factors affecting recurrence of pain after surgery for chronic pancreatitis

Parameter	p-value	Odds ratio
IV analgesics requirement	0.05	2.0 (0.99, 4.31)
Endoscopic intervention	0.04	2.2 (1.01, 4.81)

IV, intravenous.

There was no significant difference between the 2 groups regarding age at diagnosis, gender, duration of symptoms, alcohol consumption, pain type, pain severity, jaundice, weight loss, diabetes, steatorrhea, common bile duct diameter, pancreatic parenchymal calcification, pancreatic duct diameter, pseudocysts, type of surgery (LPJ or Frey’s), main pancreatic duct stricture, pancreas texture, pancreatic duct stone location, type of anastomosis, or postoperative complications (Table 1, 2).

Out of 125 patients, 19 (15.2%) had diabetes mellitus before surgery; post-surgery, diabetes improved in 5 (4.0%) patients, worsened in 9 (7.2%) patients, and newly onset diabetes mellitus was noted in 10 (8.0%) patients. Postoperatively, 71 (56.8%) patients experienced weight gain, while 10 (8.0%) experienced weight loss. Additionally, the incidence of steatorrhea increased from 23 patients to 32 patients post-surgery.

DISCUSSION

Pancreatic pain is the most common symptom of CP. Not all CP patients experience severe abdominal pain. In some, the pain is constant and intense, while in others, it is not. Constant pain can lead to anxiety, depression, increased disability, repeated hospitalization, and consequently, poor quality of life [12,13]. The mechanism behind pancreatic pain is complex and multifactorial. Several hypotheses have been proposed: “(1) inflammation in the pancreas, including damage caused by free radicals; (2) pancreatic ischemia resulting from increased pressure within the pancreatic duct or parenchyma; (3) extrapancreatic causes of pain, such as stenosis of the bile duct and duodenum due to extensive fibrosis and inflammation of the pancreas; and (4) alterations in the pancreatic nerves (changes in the neuroanatomy of pancreas, sensitization of visceral nerves, or injuries to the central nervous system) that are abnormally large or injured” [14,15]. Pain management is typically conservative, though long-term outcomes are often poor [16]. Based on the aforementioned hypotheses, LPJ and Frey’s procedure have been recognized as the two primary surgical options for managing CP.

In this study, a total of 125 patients were included, all of whom underwent surgery, resulting in complete pain relief for 43.2% over a median follow-up period of 35 months, comparable to the study by Li et al. [8] (48%), whereas Negi et al. [7] reported superior pain relief at 75%. However, Negi et al.’s [7] study included a control group with both partial and complete pain relief patients. In the current study, the control group included only patients with complete pain relief. Among those with recurrent pain, five patients required a celiac plexus block, after which they achieved pain control.

There was a significant reduction in the overall mean IFC pain score from 13.7 ± 3.3 to 2.5 ± 2.8 postoperatively. The mean postoperative IFC pain score in the pain group was 4.4 ± 2.43. Negi et al. [7] and Li et al. [8] also found significant reductions in Izbicki pain scores from a median of 46.4 before surgery to 10.0 post-operation, and a preoperative score of 51.8 to 11.8, respectively. To our knowledge, no other studies have measured recurrent CP pain using the IFC pain score to date.

Multivariate analysis revealed that patients undergoing preoperative endoscopic intervention and those requiring preoperative IV analgesics were at higher risk for pain recurrence postoperatively. This finding aligns with Ahmed Ali et al. [17], though in studies by Negi et al. [7] and Li et al. [8], preoperative opiate medication significantly correlated with pain recurrence, but endoscopic intervention did not.

Preoperative IV analgesic requirement was an independent predictor of postoperative recurrence of pain in the current study (62% vs 42%, p = 0.05 with odds ratio = 2.0), consistent with findings reported by Negi et al. [7] and Li et al. [8]. This may indicate that patients requiring IV analgesics preoperatively for pain control could have a severe or advanced form of the disease that probably did not respond well to surgical intervention. These patients may benefit from early referral for surgical evaluation.

In the current study, multivariate analysis revealed that preoperative endoscopic intervention was an independent factor significantly associated with the recurrence of pain postoperatively, similar to findings by Ahmed Ali et al. [17]. The mean IFC pain score for patients who underwent endoscopic intervention was significantly higher than that for those without intervention (3.67 vs 1.90, p = 0.001). In this study, endoscopic interventions were performed in 46 (36.8%) patients, compared to 59%, 25%, and 16% in studies by Ahmed Ali et al. [17], Negi et al. [7], and Li et al. [8], respectively. Conditions such as stenoses, strictures, and stones not amenable to endoscopic management require surgical intervention [18]. Preoperative endoscopic intervention significantly increased the risk of recurrent pain postoperatively, with a 2.2-fold increase in the risk of recurrence with any number of interventions. This underscores the importance of early referral to surgery for improved pain relief. Criteria for selecting cases for endoscopic intervention should be more rigorous. Considering all the factors, early surgical management seems to offer better symptomatic relief and reduced recurrence of pain, though the definition of early surgery needs standardization. The feasibility of an early surgical approach depends on reducing financial barriers, apprehension about surgery, and inherent surgical risks to a level comparable with endoscopic management.

In this study, 12 (9.6%) patients presented with jaundice; 10 underwent endoscopic intervention followed by surgery (biliary drainage in 7 patients and cholecystectomy in 3 patients), while 2 patients proceeded directly to surgical biliary drainage. Limitations of this study include its retrospective nature (most patients were operated on before the study began, and variables were collected from retrospective records), a small sample size, and a questionnaire-based assessment of pain.

In conclusion, surgical drainage procedures are an effective treatment option for alleviating pain in patients with CP. Patients requiring IV analgesics preoperatively or those who underwent endoscopic interventions exhibited a higher risk of recurrent pain. Our study found no evidence of neuropathic pain as a cause of pain recurrence following surgery for CP. Future randomized, large sample, prospective studies are necessary to further substantiate these observations (e.g., evaluating whether early surgical intervention may be beneficial for certain patient groups; examining the incidence and causes of recurrent pain post-surgery; determining whether postoperative long-term complications like anastomotic strictures influence pain recurrence; assessing whether there is rapid progression of endocrine or exocrine dysfunction post-surgery).

Funding Statement

FUNDING None.