Nonspecific Supportive Therapy

Analgesic medications are still the most commonly adopted method for pain relief. Although the reluctance to use narcotics is understandable, the primary focus should be on the relief of pain and not the risk of dependence. All management guidelines for pain in CP follow the World Health Organization’s three-step ladder for the treatment of chronic pain. The treatment should be initiated with monotherapy, either acetaminophen or nonsteroidal antiinflammatory drug, or both. If there is insufficient effect, a combination therapy—peripherally acting medication with centrally acting medication—is considered. A nonopioid analgesic is combined with a weak opioid, such as tramadol. A simple pain diary with a 10-cm visual analog scale is useful, both as a baseline quality-of-life assessment and for titration of the analgesics. Analgesics are coupled with a neuroleptic antidepressant for concurrent depression. In this regard, tricyclic antidepressants, selective serotonin reuptake inhibitors, and combined serotonin and norepinephrine reuptake inhibitors (duloxetine) are definitely worth a therapeutic trial. In a recent placebo-controlled trial, pregabalin was shown to be an effective adjuvant therapy for pain in patients with CP.

A recent pilot study evaluated the utility of intrathecal narcotic infusion pumps as an alternative to aggressive surgical interventions such as total pancreatectomy. In this study, pumps were offered to 13 patients who were deemed to have intractable pain characterized by persistent severe pain (median duration of 6 years) despite high-dose narcotics, frequent hospitalization, jejunal feedings, and endoscopic retrograde cholangiopancreatography sphincter therapy. Overall, 10 of 13 (76.9%) had a 1-year decline in pain score from 8.3 to 2.7 and median narcotic usage from 337.5 to 40 mg per day. Although the infusion pump carries risk, the potential benefits of bringing relief to these patients with intractable painful CP cannot be ignored.

Enzyme Supplementation

The suspected mechanism for pain relief after administration of oral pancreatic enzymes is through negative feedback inhibition to the pancreas. In CP, consequent to damage to the acinar cells, there is a diminished secretion of pancreatic trypsin and hence, insufficient denaturing of the cholecystokinin-releasing peptide. This mechanism leads to uninterrupted potentiation of cholecystokinin (CCK), which causes hyperstimulation of the pancreas and leads to basolateral secretion rather than apical secretion of pancreatic enzymes, or both. Increased pressure in the setting of pancreatic ductal obstruction causes pain. By supplementing active proteases to the feedback-sensitive portion of the small bowel (duodenum), CCK secretion, and hence pancreatic secretion, is reduced. To date, there are six randomized trials wherein two studies using a nonenteric-coated enzyme preparation reported benefit, and the other four studies using an enteric-coated capsule showed no effect on pain in CP. The enteric-coated preparations are not active in the duodenum and therefore cannot degrade CCK-releasing factor. The nonenteric-coated preparations should be administered along with acid suppressants such as a proton pump inhibitor or H ₂ receptor blocker, because they are otherwise susceptible to degradation in the stomach by gastric acids before they reach the duodenum. A metaanalysis of the six randomized double- blind placebo-controlled trials involving both enteric-coated and nonenteric-coated preparations for the treatment of CP showed no real benefit of either preparation. Nevertheless, the role of pancreatic enzymes in mitigating pain still remains unclear. However, experts recommend a 6-week trial of nonenteric pancreatic enzyme for small-duct disease. If patients respond, they should continue until a 6-month pain-free interval has been achieved, because nearly 50% of patients relapse upon withdrawal of the supplements.

Octreotide

Octreotide, a synthetic long-acting somatostatin analogue, inhibits pancreatic secretions directly and also indirectly by blocking CCK and secretin release. In experimental models it has been shown to have antiinflammatory properties and to alter the cytokine milieu; it may also protect pancreatic cells. Octreotide is known to lower the intraductal pressure in pancreatic ductal obstruction and decrease proteolysis. A more recent pilot study showed that a once-monthly long-acting octreotide depo preparation is a useful substitute for the three times daily short-acting octreotide in the management of pain in CP. Experts, however, have warned of the increased risk of hypoglycemia or poorer glucose control in persons with diabetes. Since octreotide predisposes to biliary stasis, patients need to be closely monitored for biliary stones. Overall, octreotide therapy has not been accepted widely due to the above reasons and because its effectiveness could not be demonstrated consistently.

Antioxidant Therapy

Free radicals and oxidative stress have been implicated in the pathogenesis of CP. A decreased plasma concentration of antioxidants due to reduced micronutrient intake (vitamin E, riboflavin, choline, magnesium, copper, manganese and sulfur) has been demonstrated in an Indian study. This result was attributed to the dietary modifications secondary to pain as well as to reduced caloric intake, thereby contributing to oxidative stress both in alcoholic and nonalcoholic pancreatitis. A modest improvement in pain with an antioxidant cocktail (L-methionine, β-carotene, vitamin C, vitamin E, and organic selenium) has been demonstrated in a randomized controlled study. The benefit of combined antioxidant therapy for 20 weeks was also reported by a different group. Allopurinol, which reduces the formation of oxygen radicals by inhibiting xanthine oxidase, was investigated in a crossover double-blind study and was found to be effective. Another study in which allopurinol was combined with intramuscular pethidine showed a significantly superior effect as compared with pethidine alone. However, due to lack of other effective therapies and at least one good randomized control trial, antioxidants are currently administered to most patients with CP.

Nerve Block for Pain Relief

Unfortunately, a substantial group of patients have CP that is refractory to conventional treatment, and other forms of pain relief have been explored. In this regard, celiac plexus blockade (CPB) and celiac plexus neurolysis (CPN) are used to disrupt the signaling of the pancreatic nociceptive afferent to the spinal cord in an effort to diminish pancreatic-induced abdominal pain. CPN refers to permanent ablation of the celiac plexus, often achieved with alcohol or phenol administered with local anesthetic such as bupivacaine. However, CPN is restricted to control of refractory pain for malignant indications, given the potential risk of retroperitoneal fibrosis. CPB, on the other hand, refers to the temporary inhibition of celiac plexus achieved with a corticosteroid in combination with bupivacaine for a more sustained analgesic effect.

Before the advent of widespread use of computed tomography (CT) and endoscopic ultrasound (EUS), CPB was performed through a posterior (blind translumbar) approach, with a risk of serious complications including paraplegia and pneumothorax in 1% of cases. This risk led to the emergence of the anterior approach under the guidance of transcutaneous, CT-guided, or EUS-guided techniques. EUS-guided CPB has been shown to be superior to fluoroscopic-guided percutaneous technique. Better localization of the celiac plexus and targeted injection into the celiac plexus allows substantial pain relief for a greater duration of time. In a small random prospective comparison of 22 patients managed with either EUS-guided CPB or CT-guided CPB, EUS-guided CPB provided more initial (50% compared with 25%) and persistent (30% compared with 12%) pain relief than CT-guided CPB. In a follow-up prospective study of 90 patients with refractory CP pain, all of whom received EUS-guided CPB, the same investigators reported that pain reduction was achieved in 55% patients at a mean follow-up of 8 weeks, whereas 10% experienced persistent relief at 24 weeks. However, EUS-guided CPB is less effective in younger patients as well as in those with previous pancreatic surgery. This result was further corroborated by a recent metaanalysis of six studies of EUS-guided CPB (n = 221 patients), which reported relief of pain by CPB in 51.5%.

From these studies, it was felt that EUS-guided CPB, a relatively effective outpatient procedure, for CP pain. CPB may provide temporary respite from pain for patients and also allow some temporary downward titration of dose and potency of narcotic analgesics. A recent prospective randomized trial comparing bilateral (two injections) to central (one injection) EUS-guided CPB did not show a difference in duration or time to onset of pain relief between the two arms of the trial. Identification of predictors for response to CPB is essential for appropriate selection of patients. Until then, EUS-guided CPB should be restricted to treating flares of chronic pain in patients with otherwise limited therapeutic options as it can be rarely associated with major complications.

Thoracoscopic-directed sectioning of splanchnic nerves (either unilateral or bilateral approach) is another neurolysis technique that has been explored. Previous opioid use, which is common in this group of patients, is known to impact analgesia after splanchnicectomy. Splanchnicectomy may not be feasible in all patients and, because of its poor long-term efficacy, it is used rarely and as a last resort.

Endoscopic Therapy for Pain

Elevated pressure in the main pancreatic duct allegedly causes changes in parenchymal blood flow and pH, resulting in tissue ischemia and pain. There is an inconsistent relationship between pancreatic anatomy and pain severity. The aim of endoscopic therapy is to relieve the obstruction of the pancreatic duct and to reduce pressure in the pancreatic duct and pancreas. Pancreatic duct decompression via endoscopic retrograde cholangiopancreatography includes the dilatation and stenting of pancreatic duct strictures, which is usually preceded by pancreatic sphincterotomy, and removal of obstructing pancreatic duct stones. Endoscopic therapy is most appropriate in the presence of a single obstructing lesion (stricture or stone), with ductal dilation upstream from the site of obstruction, and preferably with the stone smaller than 1cm that is located in the main pancreatic duct, not too numerous or tightly impacted, and easily amenable to endoscopic manipulation. Other indications for endoscopy include drainage of pseudocyst, treatment of a benign stricture of the distal bile duct due to compression from the fibrotic process in the head of the pancreas, or treatment of pancreatic duct disruption.

In one of the largest series consisting of 1018 retrospectively identified patients followed for 5 years, endoscopic intervention (pancreatic stricture dilatation, stone extraction, or pancreatic duct sphincterotomy) resulted in pain relief in 86% in the entire group but only 65% in an intention-to-treat analysis. Over this same time, one-quarter of the patients required surgery because of failure of endoscopic therapy. The pain secondary to tropical pancreatitis seems to respond better to endoscopic therapy than does pain from alcoholic pancreatitis.

Extracorporeal shockwave lithotripsy (ESWL) is useful for rapid fragmentation of pancreatic ductal stones to facilitate endoscopic extraction. A metaanalysis of 17 studies concluded that ESWL is effective for the relief of main pancreatic duct obstruction and amelioration of pain in chronic calcific pancreatitis in combination with endoscopic therapy. A more recent randomized trial that compared ESWL alone to ESWL followed by endoscopic removal of stones found equal efficacy in pain relief between the two arms of the study in patients with chronic calcific pancreatitis. The duration of hospital stay was shorter and the need for subsequent invasive procedures was smaller in ESWL alone, resulting in better cost effectiveness (three times lower cost in the ESWL-alone group). The investigators speculated that ESWL may have a “stunning” effect on nociceptive neurons or some other mechanisms of pain in addition to the obvious dissolution of stone. They also commented that patients with calcifications confined to the head of the pancreas are most likely to benefit from this treatment.

Intraductal lithotripsy, although extremely popular for the management of difficult common bile duct stone, is rarely used for managing pancreatic calcifications. The success rate is less than 10% for pancreatic ductal stones. A larger multicentric trial reported a complication rate of nearly 12%, which is three times the complication rate for biliary lithotripsy. Therefore, intraductal lithotripsy is used as a second-line option in cases in which ESWL fails to fragment the obstructive stones.

An alternative to ESWL involves the use of endoprostheses or stents placed in the pancreatic duct endoscopically. Three large retrospective studies have established the utility of stents in pain relief. The latest study with a longer follow-up period concluded that 70% of patients with severe CP who respond to pancreatic stenting maintain this response after definitive stent removal. However, a significantly higher restenting rate was observed in patients with CP and pancreas divisum. The benefit of placing multiple sequential stents has been recently evaluated. During a mean follow-up of 38 months, 84% of patients with multiple stents (median of three stents) were asymptomatic, and only 11% experienced a symptomatic recurrence. Thus, endoscopic multiple stenting of a dominant pancreatic duct stricture seems to be feasible and promising.

Endoscopic therapy can be technically demanding with results that are highly operator-dependent; therefore, reports from expert centers cannot be easily extrapolated to centers with smaller volume or less experience.

Surgery

For patients who do not respond to medical therapy, surgical therapy is emerging as a viable option, particularly for patients with a clear correctible anatomic abnormality. Goals of surgery are to decompress the obstructed ducts (to eradicate pain) and to preserve pancreatic tissue and adjacent organs (to preserve function). The modified Puestow procedure, or lateral pancreaticojejunostomy, is a relatively simple procedure that is commonly performed. Ductal strictures are incised, allowing any ductal stones to be removed. Short-term pain relief is seen in about 80% of patients; however, long-term relief drops to 50% in about 5 years.

The classic Whipple procedure is also used for the excision of the inflammatory pancreatic head masses. It is curative, with complete resolution of symptoms in groove pancreatitis, and is also considered if there is a duodenal obstruction or if cancer cannot be excluded preoperatively. However, the Whipple procedure sacrifices an extensive portion of the functional pancreatic parenchyma. There have been many modifications to this procedure, such as the duodenum-preserving pancreatic head resection (Beger’s procedure) and the Frey procedure, which aim to preserve the duodenum and pylorus. Both procedures are associated with low morbidity and mortality and demonstrate a high rate of sustained pain relief and return to productivity, in spite of the difference in the amount of pancreas excised. Randomized trials comparing these two procedures found equal efficacy although beger’s procedure is technically more demanding. In general, although the immediate pain relief is similar in patients receiving the modified Puestow procedure, long-term relief seems to be superior at the expense of more perioperative and postoperative complications. A recent analysis of mortality after pancreatectomy for CP showed that proximal pancreatectomy was associated with a 2.5-fold increased risk of death compared with distal pancreatectomy.

Recently, randomized trials have compared endotherapy to surgery for the treatment of painful large-duct CP. A prospective randomized controlled trial concluded that at 1 year, pain relief was similar in both groups. At 5 years, however, more patients who underwent surgery had complete absence of pain and greater weight gain than patients who underwent endotherapy (34% vs 15% and 47 vs 29%, respectively). In this study, surgery encompassed more than just a drainage procedure, and endoscopic therapy did not include lithotripsy, which is currently the cornerstone of endoscopic drainage. But these findings were corroborated more recently by the Amsterdam group in a randomized trial comparing endoscopic lithotripsy to surgical drainage of pancreatic duct. In this study, although the rate of complications, length of stay, and changes in pancreatic function were similar in both groups, patients receiving endoscopic treatment required more procedures than the patients treated surgically (a median of 8 compared with 3 surgeries). At the end of the 24-month follow-up period, complete or partial pain relief was achieved in 32% of patients assigned to endoscopic drainage, as compared with 75% of patients assigned to the surgery group. The same investigators published their latest 5-year outcome in a recent study, which further confirmed that surgery at the time of initial presentation was superior to lithotripsy and stenting, not only in terms of pain relief but also in terms of complications and required reinterventions, without being associated with higher costs. These randomized trials, although criticized for methodological flaws, suggest that surgical therapy is superior and more durable compared with endoscopic therapy for selected CP patients with dilated pancreatic duct.

To summarize, operative approaches have dramatically evolved over the last few years, in that the head of the pancreas has been universally accepted as the nidus of chronic inflammation. The final choice of the appropriate procedure, however, should be guided by the experience of the individual surgeon and the center.

Total Pancreatectomy and Autologous Islet Cell Transplantation

The final surgical option is a total pancreatectomy in conjunction with harvesting islet cells and reinfusing these isolated cells through the portal vein into the liver, a procedure that is available in very few highly specialized pancreatic centers in the world. This procedure is an attractive option for patients with hereditary pancreatitis, for prevention of pancreatic cancer that can be associated with CP, for the preservation of some endocrine function when eventual glandular depletion is inevitable, and as a last resort for treatment of refractory pain. Currently, the procedure is being performed in patients with painful refractory small-duct disease (pancreatic duct is not dilated). Some experts consider this aggressive life-changing intervention as a trade of chronic refractory pain for lifelong brittle diabetes with all its inherent downstream complications. In adults, 60% to 80% of patients who have undergone total pancreatectomy and autologous islet cell transplantation (TP/AICT) have a marked reduction in narcotic use. Insulin independence is achieved in 40% of patients. Previous pancreatic surgeries adversely affect the total yield and reduce the rate of postoperative insulin independence. A recent study concluded that more severe histopathology staging of CP is associated with lower islet yield. Therefore, the investigators advocate that TP/AICT should not be delayed in patients with painful CP; otherwise, progressive damage to the pancreas may limit islet yield and increase the risk of diabetes. If results are further improved, TP/AICT may become a promising option for those with small-duct diffuse inflammatory disease and at the present time more studies from other centers are needed to see if the results can be duplicated.

Other Modalities of Pain Relief

Yoga resulted in reduced pain, reduced use of analgesics, increased weight gain, and an improvement in quality of life in a study comparing patients with CP who were randomized to usual care by their physicians or to usual care plus yoga three times per week for a 12-week period.

Among new medications, CCK-receptor antagonists seem to be promising. Proglumide, a nonspecific CCK-receptor antagonist, was noted to not only reverse tolerance to morphine and potentiate its effects but also to ameliorate pain on its own. A few years later the therapeutic efficacy of loxiglumide, a CCK-A antagonist, was reaffirmed by multicenter dose response study in Japan.

The antiinflammatory effects of radiotherapy were recognized nearly 5 decades ago in a Russian study showing sustained good response after 2 years in 66% of the 56 patients with CP who were treated with radiation. A more recent prospective pilot trial of 15 consecutive patients treated with a single 8 Gy dose of radiation applied to the pancreatic area demonstrated that a single low dose of radiation was effective in preventing new flare-ups, in addition to alleviating pancreatic pain and improving quality of life in severely symptomatic patients, without significant side effects.