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Opioids represent the next stage in the treatment of pancreatic pain. Opioids can be classified by their actions: agonist (e.g. morphine, hydromorphone, fentanyl), partial agonist (e.g. buprenorphine), agonist/antagonist (e.g. pentazocine), and antagonist (e.g. naloxone). Pure opioid agonists are the most potent analgesics, and they are stronger pain relievers than non‐opioids.

Opioids acts by binding to opioid receptors (μ₁ and μ₂, κ and δ) found in the central, peripheral, and autonomic nervous system. They induce analgesia by inhibiting neurotransmitter release on presynaptic neuronal terminals in the spinal cord and inhibition of postsynaptic neurons preventing the ascending transmission of the pain signal. Tramadol possesses both weak opioid agonist activity and inhibition of serotonin and norepinephrine uptake. This dual mechanism of action is considered to underlie its effectiveness in some pain patterns that are poorly responsive to other treatments. Tramadol has been shown to be superior to morphine, with fewer gastrointestinal side effects for the same level of analgesia.

Traditionally, opioids have been avoided as pain treatment in AP because of the fear that they may mask the manifestations and clinical course of the disease and increase pain due to their spasmogenic effect, which in turn increases intraluminal pressure in the sphincter of Oddi. However, the clinical significance of this increased pressure is uncertain, because many studies are anecdotal observations, with small numbers of participants without known pancreatic disease. In manometric studies only high doses of morphine have been able to significantly increase basal pressure in the sphincter of Oddi and may compromise bile duct emptying. However, no evidence is available that this possible morphine spasmodic effect on the sphincter of Oddi would induce a worse clinical evolution or cause complications in AP. In summary, there is not enough evidence to support the contraindication or limitation of morphine for AP pain treatment.

Usually, meperidine (pethidine) is selected rather than morphine, which has been traditionally avoided based on its presumed spastic action on the sphincter of Oddi. Nevertheless, no studies have directly compared their effects on sphincter of Oddi manometry in AP and no randomized controlled trials exist comparing morphine to meperidine in the treatment of AP. On the other hand, it is reported that the meperidine metabolite normeperidine increases the risk of seizures, especially in patients with renal failure, a well‐known complication in AP. In addition, although meperidine has a short half‐life of 3–4 hours, its toxic metabolite has a half‐life of up to 20 hours in healthy subjects. For these reasons, continuous infusion of meperidine is not recommended. In contrast, morphine’s plasma elimination half‐life is approximately 2 hours and 2.4–6.7 hours for its metabolite, making toxicity less likely. Finally, drug–drug interactions can be problematic for meperidine. For example, meperidine is contraindicated in patients concurrently taking monoamine oxidase inhibitors because of possible hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension. Also, plasma levels of meperidine may quickly reach toxic levels in patients on some antiretrovirals (i.e. ritonavir). Morphine has fewer drug interactions, the main interaction being the prolonged effect seen with concomitant use of tricyclic antidepressants. Nevertheless, the American Pain Society recommends parenteral meperidine as a reasonable choice only when there is intolerance to all other opioids and/or very brief analgesia is needed.

Sufentanil is a fentanyl analog and, like fentanyl, has no active metabolites. It is ten times more potent than fentanyl and 100 times more potent than morphine but has the highest therapeutic index. This high therapeutic index may be clinically relevant, because of a less frequent incidence of respiratory depression with sufentanil compared with morphine.

Parenteral administration of opioids is recommended in AP. However, because of the short half‐life (less than four hours) of opioids, if continuous analgesic effect is required continuous perfusion would be desirable (see Table 9.1).

Opioids have the potential to produce side effects including nausea, constipation, urinary retention, itching, pupillary constriction, cognitive impairment, and respiratory depression. With long‐term use, tolerance and physical and psychological dependence may develop. Respiratory depression is the most important side effect, especially in severe AP, where opioids may contribute to the occurrence of respiratory failure or aggravate it when it is already present. In the gut, opioids exert their action on the enteric nervous system, where they bind to the myenteric and submucosal plexuses, causing dysmotility, decreased fluid secretion, and sphincter dysfunction, which all lead to opioid‐induced bowel dysfunction. In the clinic, this is reported as nausea, vomiting, gastroesophageal reflux‐related symptoms, and constipation. Compromised motor function is not only a hallmark of severe pancreatitis, but even more so is assumed to play a key role in the pathogenesis of complications, particularly by promoting bacterial translocation and infection of necrotic tissue. Opiates may induce or amplify motility disturbances, which in this patient group are particularly undesirable [7].

However, opioids have been demonstrated to be effective and safe analgesics. None of the randomized controlled trials available reported an increase in the adverse event rate for opioids compared with the placebo or non‐opioid groups. No difference was demonstrated in the risk of pancreatitis complications between opioids and other pain relief treatments [8]. Only five single‐center randomized clinical trials involving a total of 227 patients assessing the effectiveness of opioid drugs for treating AP pain are available.

Intramuscular injection of buprenorphine (0.3 mg) was as effective as intramuscular pethidine (100 mg) [9], while constant intravenous buprenorphine infusion (2.4 mg per 24 hours) was more effective than intravenous procaine (2 g per 24 hours) for pain relief in AP [10]. Bolus intravenous injection of pentazocine (30 mg every 6 hours) was more effective in reducing pain score than intravenous infusion of procaine (2 g per 24 hours) [11]. Transdermal fentanyl significantly decreased pain intensity at 36 and 45 hours after application as compared with placebo [12]. Subcutaneously administered morphine (10 mg every 4 hours) did not show a reduction in pain intensity as compared with intravenous metamizole (2 g every 8 hours i.v. with slow perfusion) in AP [3].

Overall, opioids may be an appropriate treatment option in relief of moderate or severe pain in AP. Opioid use is suggested, at the lowest effective dose, for pancreatitis pain management. Acetaminophen and NSAIDs are recommended as an adjunct to opioid therapy to decrease pain intensity and opioid consumption. PCA with systemic opioids provides greater pain relief and higher patient satisfaction than analgesia given as required by medical staff. However, basal infusions of opioids increase the risk of respiratory depression [13]. The opioid antagonist naloxone is the definitive antidote for overdose of opioids.