REVIEW ARTICLE

Treatment of acute abdominal pain in the emergency room: A systematic review of the literature C. Falch1*, D. Vicente2*, H. Häberle3, A. Kirschniak1, S. Müller1, A. Nissan4,5,6, B.L.D.M. Brücher4,5,7 1 2 3 4 5 6 7

Surgery, University of Tübingen, Germany Department of Surgery, Walter Reed National Military Medical Center, Bethesda, USA Department of Anesthesiology, University of Tübingen, Germany INCORE, International Consortium of Research Excellence of the Theodor-Billroth-Academy®, Germany – Israel – Serbia – USA Theodor-Billroth-Academy®, Germany – Israel – USA Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Bon Secours Cancer Institute, Richmond, USA

Correspondence Björn L.D.M. Brücher E-mail: [email protected] Funding sources None. Conflicts of interest None declared. This paper contains original material that has not been previously published. * Equal contribution. Accepted for publication 12 December 2013 doi:10.1002/j.1532-2149.2014.00456.x

Abstract Appropriate pain therapy prior to diagnosis in patients with acute abdominal pain remains controversial. Several recent studies have demonstrated that pain therapy does not negatively influence either the diagnosis or subsequent treatment of these patients; however, current practice patterns continue to favour withholding pain medication prior to diagnosis and surgical treatment decision. A systematic review of PubMed, Web-ofScience and The-Cochrane-Library from 1929 to 2011 was carried out using the key words of ‘acute’, ‘abdomen’, ‘pain’, ‘emergency’ as well as different pain drugs in use, revealed 84 papers. The results of the literature review were incorporated into six sections to describe management of acute abdominal pain: (1) Physiology of Pain; (2) Common Aetiologies of Abdominal Pain; (3) Pre-diagnostic Analgesia; (4) Pain Therapy for Acute Abdominal Pain; (5) Analgesia for Acute Abdominal Pain in Special Patient Populations; and (6) Ethical and Medico-legal Considerations in Current Analgesia Practices. A comprehensive algorithm for analgesia for acute abdominal pain in the general adult population was developed. A review of the literature of common aetiologies and management of acute abdominal pain in the general adult population and special patient populations seen in the emergency room revealed that intravenous administration of paracetamol, dipyrone or piritramide are currently the analgesics of choice in this clinical setting. Combinations of non-opioids and opioids should be administered in patients with moderate, severe or extreme pain, adjusting the treatment on the basis of repeated pain assessment, which improves overall pain management.

1. Introduction Treating acute abdominal pain in the emergency room (ER) is one of the most frequent tasks faced by surgeons. Appropriate analgesia requires evaluation of the individual patient’s pain, as well as a broad base of knowledge of the pathophysiology of common causes of abdominal pain and the pharmacology of appropriate analgesic agents. Currently, there is no clear © 2014 European Pain Federation - EFIC®

consensus regarding the timing of neither analgesia nor the type of analgesic medications that should be used to effectively manage acute abdominal pain. This uncertainty largely stems from concerns that prediagnostic analgesia may confound patient evaluation, particularly the abdominal examination. This paper is intended to provide physicians-in-training and experienced surgical specialists with an overview of modern management of acute abdominal pain in adult Eur J Pain •• (2014) ••–••

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Acute abdominal pain therapy in emergency patients

What’s already known about this topic? • Currently, there is no clear consensus regarding the timing of analgesia, and the type of analgesic medications that should be used to effectively manage acute abdominal pain in the emergency room. Database? • Medline, PubMed, Web-of-Science and TheCochrane-Library. What does this study add? • Clinical and practical evidence that the intravenous administration of paracetamol, dipyrone or piritramide are currently the analgesics of choice in the emergency room treating patients with acute abdominal pain. • Combinations of non-opioids and opioids should be administered in patients with moderate, severe or extreme pain, adjusting the treatment on the basis of repeated pain assessment, which improves overall pain management.

patients based on results of a comprehensive published literature review.

2. Methods A systematic review of PubMed, Web-of-Science and TheCochrane-Library from 1929 to 2011 was carried out using the terms (number of results of papers) ‘acute surgical abdomen (n = 13,840), ‘acute abdominal pain’ (n = 17,324), ‘pain therapy’ (n = 193,129), ‘pain treatment’ (n = 354,789), ‘paracetamol’ (n = 17,842), ‘metamizole’ (n = 1504), ‘dipyrone’ (n = 1319), ‘NSAID’ (n = 177,007), ‘non-opioid analgesics’ (n = 279,034), ‘opioid analgesics’ (n = 6531), ‘emergency’ (n = 200,416), ‘emergency room’ (n = 13,009), ‘emergency unit’ (n = 12,809), ‘pre-operative pain therapy’ (n = 4351), ‘rescue service’ (n = 1040), ‘pain and pregnancy’ (n = 15,683), ‘opioiddependence’ (n = 19,359), ‘drug addict’ (n = 346,827), published in the English and German languages. Adding the term ‘review’ produced a significant decrease in search results according to the type of search term: ‘acute surgical abdomen’ (n = 1954), ‘acute abdominal pain’ (n = 1874), ‘pain therapy’ (n = 3236), ‘pain treatment’ (n = 50,147), ‘paracetamol’ (n = 1879), ‘metamizole’ (n = 71), ‘dipyrone’ (n = 66), ‘NSAID’ (n = 18,851), ‘non-opioid analgesics’ (n = 24,194), ‘opioid analgesics’ (n = 92,617), ‘emergency’ (n = 22,792), ‘emergency room’ (n = 1104), ‘emergency unit’ (n = 1241), ‘preoperative pain therapy’ (n = 654), ‘rescue service’ (n = 113), ‘pain and pregnancy’ (n = 2214), ‘opioid-dependence’ (n = 2016), ‘drug addict’ (n = 37,823). Including a combination of the terms above as well as adding the search terms ‘physiology’

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and ‘abdominal pain physiology’ under the category of reviews dealing with current clinical practices of acute abdominal pain management both pre- and post-diagnosis revealed 84 papers.

3. Results The results of the literature review are incorporated into six sections to describe management of acute abdominal pain: (1) Physiology of Pain; (2) Common Aetiologies of Abdominal Pain; (3) Pre-diagnostic Analgesia; (4) Pain Therapy for Acute Abdominal Pain; (5) Analgesia for Acute Abdominal Pain in Special Patient Populations, and (6) Ethical and Medico-legal Considerations in Current Analgesia Practices. The results of the literature review will also be used to develop a comprehensive algorithm for analgesia for acute abdominal pain in the general adult population.

3.1 Physiology of pain Acute pain is a normal and expected physiological response to an adverse chemical, temperature-related or mechanical stimulus associated with acute disease, trauma or surgery (US Federation, 1999). It thus represents a physiological protective mechanism against tissue-damaging effects. After tissue damage has begun, pain largely loses its function as a warning signal and – in addition to impairing overall wellbeing – leads to stimulation of the somatic and sympathetic nervous systems (Stork and Hofmann-Kiefer, 2009). Tissue trauma releases hyperalgesic substances such as bradykinins, prostaglandins, histamines, serotonin, ‘nerve growth factor’, hydrogen ions, adenosine triphosphate (ATP), and immune cells, which lead to activation of the nociceptive system and the initiation of pain sensation (Carr and Goudas, 1999; Stork and Hofmann-Kiefer, 2009). The impulses are transferred via fast Aδ fibres and slower C fibres via the spinal cord and brainstem to the thalamus (Gallacchi and Pilger, 2001). The thalamus then acts as the central distributor and transfers the incoming pain signals to the limbic system, hypothalamus and hypophysis. The resulting stress response is associated with a catabolic state, tachycardia, hypertension, as well as nausea and vomiting (Stork and Hofmann-Kiefer, 2009). Painrelated avoidance behaviour, such as impaired mobilization and hypoventilation, may also result. In addition to the immediate hyperalgesia, chronic pain and visceral hypersensitivity may develop due to local inflammation, nociceptor sensitization and central © 2014 European Pain Federation - EFIC®

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sensitization. Hence, timely and adequate pain control will assist in decreasing pain-related complications and achieving faster recuperation, with an associated increase in patient satisfaction, quality of life and overall reduced health-care costs (Kehlet and Holte, 2001; Wilder-Smith et al., 2002; Kehlet, 2004; Reichl and Pogatzki-Zahn, 2009).

3.2 Common aetiologies of abdominal pain The term ‘acute abdominal pain’ is often used synonymously with ‘acute abdomen’; however, since acute abdomen often leads to emergency surgery, it is important to differentiate the terms (Grundmann et al., 2010). ‘Acute abdomen’ is a time-sensitive term for an acutely painful condition in the abdominal cavity, which cannot initially be specified as a nonsurgical or surgical aetiology until the final diagnostic assessment has been made (Siewert and Brauer, 2007). Acute abdomen can manifest as a complex of symptoms including ‘abdominal pain’, ‘peritoneal symptoms and/or signs’, and/or ‘disturbed circulatory regulation’, and requires emergent therapeutic intervention. In contrast, acute abdominal pain is a broader term that refers to the nociceptive pain response from both emergent acute abdominal aetiologies and more benign indolent processes. The most frequent causes of acute abdominal pain seen in the ER are nonspecific abdominal pain (22.0–44.3%), acute appendicitis (15.9–28.1%), biliary disease (2.9–14.0%), gastrointestinal perforation (2.3–15.0%), adynamic ileus (4.1–8.6%), diverticulitis (8.2–9.0%), pancreatitis (3.2–4.0%), ureteral colic (5.1%) and inflammatory bowel diseases (0.6%) (De Dombal, 1988; Attard et al., 1992; Miettinen et al., 1996; Strömberg et al., 2007). Many of the reviews on acute abdominal pain (Lankisch et al., 2006; Grundmann et al., 2010; Trentzsch et al., 2011) are based on a small number of original studies – e.g., the largest study, including more than 10,000 patients, conducted by the World Gastroenterology Organization dating from 1986, was based on data obtained from Finland (De Dombal, 1988; Miettinen et al., 1996). Actual data from Chapel Hill, which investigated the relationship between pain intensity and patient satisfaction in 88 patients who had been treated with opioid analgesics revealed no statistical correlation between pain intensity and patient satisfaction (Phillips et al., 2013); the authors concluded, that future investigations should use intensity scores together with measurement of patient satisfaction. © 2014 European Pain Federation - EFIC®

Acute abdominal pain therapy in emergency patients

3.3 Pre-diagnostic analgesia There is a prevailing view, particularly among surgeons (Graber et al., 1999; Nissman et al., 2003), that pre-diagnostic analgesia in patients with acute abdominal pain obscures the clinical symptoms and signs, and thereby has a negative effect on treatment decisions (Nissman et al., 2003). This, in turn, often leads to analgesia being initially withheld from the patient with acute abdominal pain (LoVecchio et al., 1997; Grundmann et al., 2010). These concerns on the part of the surgeon date back to the turn of the 20th century, when abdominal pain was regarded as the only constant symptom available for establishing a diagnosis, and basing a surgical decision (Cope, 1929). McHale and LoVecchio noted in 2001 that in the absence of prospective studies up to the mid-1980s, withholding of opioid pain therapy in patients with acute abdominal pain was based on dogma and belief, rather than established facts (McHale and LoVecchio, 2001). In addition to these fears, patients may receive inadequate pain therapy due to communication problems, concerns over side effects from analgesics and crowding of patients in ERs (Stork and Hofmann-Kiefer, 2009). The described fears and barriers have led to significant delays in appropriate pain management as revealed by Mills et al. who demonstrated that almost 50% of patients with abdominal pain only received pain medication more than an hour after admission to the ER (Mills et al., 2009). Ultimately, these delays and inadequate dosing of analgesia have impacted patient care and patient satisfaction. In comparison with postoperative analgesia, which has a patient satisfaction level of more than 90% (Saur et al., 2008), patient satisfaction with preoperative pain therapy remains inadequate, only 40–60% (Marinsek et al., 2007; Jawaid et al., 2009). Interestingly, this discrepancy in pre-diagnostic analgesia has not been evident in recent studies of trauma patients, in whom the focus for many decades has been directed to prompt diagnosis with laboratory and imaging studies (Jawaid et al., 2009). Evaluating the adequacy of preoperative analgesia and patient’s satisfaction at an accident and emergency department revealed that there was significantly less prescription of analgesic to patients with acute abdomen (47.1%) as compared to trauma patients (73.5%; p = 0.001) (Jawaid et al., 2009). In contrast to the described beliefs and fears, the published evidence-based literature supports prediagnostic administration of analgesia in the setting of acute abdominal pain. Several studies (Attard et al., 1992; Pace and Burke, 1996; LoVecchio et al., 1997; Eur J Pain •• (2014) ••–••

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Vermeulen et al., 1999; Mahadevan and Graff, 2000; Thomas et al., 2003; Gallagher et al., 2006; Amoli et al., 2008) and one Cochrane review published in 2007 (Manterola et al., 2007), which was updated in 2011 (Manterola et al., 2011), have demonstrated that administering analgesia for acute abdominal pain is appropriate prior to the diagnosis regardless of the aetiology of the abdominal pain. The authors of the Cochrane review concluded that the use of opioid analgesics neither increased the risk of misdiagnosis nor increased the risk of incorrect treatment decisions being made; the Cochrane reviewers furthermore stated that pain therapy may, in fact, make the clinical examination easier in patients with an acute abdomen. Based on these results, the authors of this paper recommend early pre-diagnostic administration of analgesia in the assessment and treatment of acute abdominal pain.

3.4.1 Pain intensity assessment Initial evaluation of patients with acute abdominal pain should rapidly and objectively assess the intensity of the pain in order to guide appropriate pain management. The intensity of pain is a subjective perception, which does not correlate with clinical findings, laboratory parameters or diagnostic imaging findings. In point of fact, several studies have demonstrated that the medical staff underestimate patient pain in comparison with the patient’s appraisal themselves (Striebel et al., 1992; Mäntyselkä et al., 2001; Davoudi et al., 2008). Simple and repeatable pain measurements using one-dimensional and multidimensional scales have been developed for objective assessment of individual pain perception. One-dimensional scales such as the visual analogue scale (VAS), verbal rating scale (VRS) and numerical rating scale (NRS), as well as the ‘Smiley analogue scale’ (SAS) are used in the acute setting (Fig. 1) (Todd et al., 1996; Kelly, 1998; Gallagher et al., 2001; Marinsek et al., 2007; Amoli et al., 2008; Daoust et al., 2008; Jawaid et al., 2009; Sharwood and Babl, 2009). Limitations for pain measurement include disturbances of consciousness, impaired vision and language barriers (Gallagher et al., 2001). These clinical scenarios may make it necessary to carefully select the scale used according to the patient’s unique personal circumstance. Due to its ease of use, with a low rate of error and a high level of acceptance and sensitivity, the NRS shows the best

3.4 Pain therapy for acute abdominal pain Management of acute abdominal pain for the general adult population in the ER requires different variables (Stork and Hofmann-Kiefer, 2009): (1) rapid initial evaluation of pain intensity; (2) administration of the appropriate analgesic agent by the appropriate route based on the clinical scenario; and (3) early implementation of adjuvant measures, which afterwards should be repeated for a continuous pain assessments to guide further analgesia.

A

Worst imaginable pain

No pain

B 0

1

2

3

4

5

6

7

8

9

10

Worst imaginable pain

No pain

C No pain

Mild pain

Moderate pain

Severe pain

Very severe pain

Worst imaginable pain

D

0

1

No pain

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2

3

4

5 Worst imaginable pain

Figure 1 One-dimensional pain scales depicting examples of pain ratings. Pain is assigned to a range between 0 and 100 mm (VAS), a selection of possible answers (VRS), a numerical value between 0 and 10 (NRS), or a facial expression (SAS). (A) Visual analogue scale (VAS). (B) Numerical rating scale (NRS). (C) Verbal rating scale (VRS). (D) The ‘Smiley’ analogue scale (SAS).

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results in adults (Aubrun et al., 2003; Herr et al., 2004; Gagliese et al., 2005); hence, the NRS is the objective scale recommended in this paper. 3.4.2 Route of administration Non-opioid and opioid analgesics are readily available, with various forms of administration. In all clinical scenarios, the route of administration of the analgesic agent should be determined relative to the estimated potential for enteric absorption of the delivered agent. Sympathoadrenergic stress reactions during acute pain and an increase in intraluminal pressure during adynamic ileus and intestinal obstruction to more than 30 mmHg can lead to reduced gastrointestinal motility and microcirculatory disturbances, which impair absorption of orally and rectally administered medications (Feifel, 1985; Stork and Hofmann-Kiefer, 2009). In cases of acute abdominal pain in which compromised enteric absorption is suspected, intravenous analgesic administration should be achieved in order to bypass the gastrointestinal system and attain rapid onset of effect (Feifel, 1985; Stork and Hofmann-Kiefer, 2009). Alternative parenteral administration routes, such as intramuscular injection, should be avoided given the potential risks of neural and vascular injury, but may be necessary for prompt pain relief if intravenous access cannot be obtained (Greenblatt and Koch-Weser, 1976; Müller-Vahl, 1983; Tong and Haig, 2000; Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) et al., 2008). 3.4.2.1 Opioid analgesics

Opioid medications are derived from opioid alkaloids and bind to opioid receptors both in the central nervous system as well as in peripheral tissues to provide pain relief (Stork and Hofmann-Kiefer, 2009). Each pharmaceutical opioid has a unique analgesic potency and side effect profile, which impact dosing and clinical indications for that medication. In the setting of severe acute abdominal pain, a strong-acting opioid, such as morphine, is required. Weak opioids (e.g., tramadol and tilidine) are not considered adequate first-line agents in the treatment of acute abdominal pain, given that they have a wellrecognized maximum daily dosage with attendant short duration of effect (Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) et al., 2008). Also, Pethidine (meperidine), a weak opioid, was previously used for treating acute biliary pain; however, it is no longer recommended due to the risk of accumulation of its active neurotoxic metabolite, © 2014 European Pain Federation - EFIC®

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norpethidine, and its relatively short duration of effect (Greenblatt and Koch-Weser, 1976). Piritramide, conversely, is a potent intravenous opioid with a long duration of effect, and no clinically established maximum dosage. It has demonstrated excellent results in post-operative analgesia (Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) et al., 2008); it thereby lends itself well to pre-diagnostic analgesia. As seen in Table 1, piritramide, should be administered in small doses and titrated to effect in order to keep side effects as low as possible (Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) et al., 2008; Stork and Hofmann-Kiefer, 2009). 3.4.2.2 Side effects and complications of opioid analgesics and their treatment

The wide range of tissues with opioid receptors allows for effective analgesia with opioid agents, but this also leads to potential side effects in almost all organ systems, which occur in a dose-dependent fashion (Schug et al., 1992; Tramèr, 2001; Harris, 2008; Stork and Hofmann-Kiefer, 2009). Particular to opioid dosing for acute abdominal pain, respiratory depression and nausea and vomiting are the most relevant side effects. Respiratory depression is the most feared side effect of these medications; however, concerns of causing respiratory depression are usually unfounded, as alterations in vital signs are rare (Kanowitz et al., 2006), and the pain itself is one of the most effective antagonists to this side effect (Stork and HofmannKiefer, 2009). In a retrospective analysis of some 2000 patients who received pre-hospital treatment with fentanyl, Kanowitz et al. reported that only 0.6% of the patients showed any alteration in vital signs, but the evaluation of the pain scales before and after fentanyl application revealed a significant change from 8.4 to 3.7 (p < 0.0001) (Kanowitz et al., 2006). Despite this rare occurrence, it is safe and prudent clinical practice to titrate strong opioids in order to minimize respiratory and circulatory depression. Treatment for respiratory depression and cardiovascular complications primarily involves oxygenation and ventilation, as well as circulation-stabilizing measures such as volume substitution and administration of circulatory support drugs (theodrenaline/cafedrine) as needed (Table 1). As a supplementary measure, the opioid effect can be antagonized with naloxone (Table 1) (Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) et al., 2008; Harris, 2008); however, it should be noted that at high dosages, the Eur J Pain •• (2014) ••–••

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Indication

Single dose

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3.75–22.5 mg

–

–

5.1 h

CI, contraindication; G6PD, glucose-6-phosphate dehydrogenase deficiency; SE, side effect.

20–40 mg (1–2 mL)

Spasmolytic (intravenous administration) Butylscopolamine bromide Spasmolytic, parasympatholytic

4–8 mg

1h

Nausea, vomiting

CI: known hypersensitivity SE: nausea, tachycardia, hypotension, hypertension

CI: known hypersensitivity SE: sedation, respiratory depression, hypotension, nausea, vomiting

SE: vertigo, hypotension CI: mechanical stenoses of the gastrointestinal tract, angle-closure glaucoma, myasthenia gravis

SE: angina pectoris, ventricular cardiac rhythm disturbances, palpitations CI: angle-closure glaucoma, pheochromocytoma

2.6–4.6 h CI: known hypersensitivity, pheochromocytoma, prolactin-dependent tumors, mechanical ileus, epilepsy 3.2–3.5 h CI: known hypersensitivity

70 min

4–10 h

Medication for circulatory support for opioid-induced hypotension Theodrenaline/cafedrine Hypotension refractory to 0.5–1.0 ampoule volume substitution (1–2 mL)

Ondansetron

2–5 min

Slow i.v.

0.5–1.0 ampoule (1–2 mL) slowly i.v. (1 mL/min)

Blockade of central 5-HT3 receptors

Inhibition of central dopamine and serotinin-3 receptors

0.1 mg every 2 min, depending on effect

Slow i.v. (10 mg/min) or short infusion → titrate!

20–30 min 1.8–4.6 h SE: agranulocytosis (very rare) Short infusion for 15 min; CI: known hypersensitivity, hypotension, hypotension with rapid dyshematopoiesis, G6PD deficiency, infusion acute intermittent hepatic porphyria, renal insufficiency (dose reduction required)

Short infusion for 15 min; do not mix with other drugs

Remarks

5000 mg

CI: known hypersensitivity, severe disturbance of liver function (e.g., in chronic alcohol abuse), G6PD

Relevant SE and CI

10–15 min

1–2 h

Half-life

4000 mg

Maximum daily Onset of dosage effect

Medications to treat opioid-induced nausea and vomiting (intravenous administration) Metoclopramide Nausea, vomiting 10 mg 30 mg

Opioid antagonists (intravenous administration) Naloxone Opioid antagonism in states of central nervous sedation (respiratory depression)

Strong-acting opioid analgesics (intravenous administration) Piritramide To be used in combination with non-opioid analgesics in moderate to extreme pain

Non-opioid analgesics (intravenous administration) Paracetamol Sole agent for mild pain. 500–1000 mg (acetaminophen) Should be used in combination with opioid for moderate to extreme pain. Dipyrone (metamizole) Sole agent for mild pain. 1000–2500 mg Should be used in combination with opioid for moderate to extreme pain.

Agent

Table 1 Analgesics, supplements and medications used to treat SEs and complications of analgesics for acute abdominal pain in adults in the emergency room.

Acute abdominal pain therapy in emergency patients C. Falch et al.

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narrow therapeutic window for naloxone causes a reduction in the analgesic effect of opioids in the central nervous system, and can be associated with significant exacerbation of pain for the patient. Nausea and vomiting are common side effects of opioid analgesia. Treatment for these side effects depends on the receptors involved, and is mainly based on treatment of post-operative opioid-related nausea and vomiting (Tramèr, 2001; Apfel et al., 2004; Büttner et al., 2004; Harris, 2008). Ondansetron and metoclopramide, as seen in Table 1, are effective agents to treat opioid-induced nausea and vomiting (Tramèr, 2001; Apfel et al., 2004; Büttner et al., 2004; Wallenborn et al., 2006). Alternative agents to treat narcotic-associated nausea and vomiting in this setting include droperidol, haloperidol and dexamethasone. For patients with treatment-resistant symptoms, the use of combinations of agents to achieve synergistic effects has been discussed (Harris, 2008; Rittner and Brack, 2011). 3.4.2.3 Non-opioid analgesics

Non-opioid analgesic agents are divided into acidic and non-acid anti-pyretic analgesics (Brune and Zeilhofer, 1999). Acidic anti-pyretic analgesics mainly accumulate in tissues with a low pH, such as tissue with active inflammatory processes, the kidneys and the stomach, whereas non-acidic analgesics distribute to all tissues (Brune and Zeilhofer, 1999). The main representatives of acidic anti-pyretic analgesics are non-steroidal anti-inflammatory drugs (NSAIDs) (Brack et al., 2004). Non-acidic anti-pyretic analgesics include pyrazolones [e.g., dipyrone (metamizole) ] and anilines [e.g., paracetamol (acetaminophen) ] (Brack et al., 2004). These non-opioid medications induce both central and peripheral analgesic effects by inhibiting cyclooxygenase and reducing prostaglandin (PG) synthesis (Stork and Hofmann-Kiefer, 2009; Toussaint et al., 2010). In contrast to the majority of the non-opioid analgesics currently available, paracetamol and dipyrone can be administered parenteral (Bannwarth and Péhourcq, 2003; Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) et al., 2008) with rapid onset of action, and thereby represent the two preferable non-opioid analgesics in patients with acute abdominal pain. As seen in Table 1, these non-opioid medications have unique analgesic, anti-pyretic and antiinflammatory effects, as well as adverse side effect profiles and contraindications (Elia et al., 2005; McGettigan and Henry, 2006; Stork and HofmannKiefer, 2009; Toussaint et al., 2010; Zahn et al., 2010). © 2014 European Pain Federation - EFIC®

Acute abdominal pain therapy in emergency patients

The recommended dosing to achieve pain relief with a single dose is described in Table 1, as well as the maximum daily doses to mitigate renal toxicity with dipyrone (Abu-Kishk et al., 2010) and hepatotoxicity with paracetamol, respectively. Combinations of non-opioids, particularly NSAIDs and paracetamol, remain controversial. Lange et al. analysed 25 randomized controlled trials and investigated if a combination of different non-opiods would have an advantage of an improved analgesia regimen and/or would lead to a reduction of opiod-related adverse effects (Lange et al., 2007). Only three out of 25 trials revealed improved analgesic efficacy and therefore the authors concluded that a combination of non-opiod-analgesics cannot be recommended at the present time. In contrast, combinations of opioids with non-opioid analgesics improve the quality of analgesia and allow for a reduced opioid dosage, with an overall reduction in opioid-associated side effects such as nausea, vomiting and respiratory depression (Dahl et al., 1990; Elia et al., 2005; Marret et al., 2005; Stork and Hofmann-Kiefer, 2009). 3.4.2.4 Significant side effects of non-opioid analgesics and their treatment

While most side effects of non-opioid medications are relatively benign, particularly for single-dose administration of the agent, there is a known incidence of less than one case in 1,000,000 of agranulocytosis after administration of dipyrone (Ibáñez et al., 2005). For this reason, dipyrone is not available in all countries, and typically requires prescription in countries where it is available. Initial patient evaluation should rule out a history of dyshematopoesis, when possible, prior to administering dipyrone (Bannwarth and Péhourcq, 2003). 3.4.2.5 Spasmolytics

In cases of colicky abdominal pain such as biliary or ureteral colic, spasmolytic (parasympatholytic) agents such as butylscopolamine bromide (Table 1) should be considered (Makharia, 2011). There is no clear consensus in the literature regarding the optimal analgesic agent for acute colicky abdominal pain prior to diagnosis. While butylscopolamine demonstrated excellent analgesia for biliary colic (Tytgat, 2008), it was not as effective in relieving pain in renal colic patients when compared to dipyrone (p < 0.05) (Stankov et al., 1994). Further, combinations of butylscopolamine and dipyrone did not potentiate analgesia (Edwards et al., 2002). In this light, butylscopolamine should not be Eur J Pain •• (2014) ••–••

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used as a first-line analgesic agent in treating acute abdominal pain, but rather as a supplementary measure for colicky abdominal pain after initial administration of analgesia.

3.4.2.6 Appropriate timing and dosing of analgesics, and reassessment of pain intensity

Once the patient-reported pain intensity has been assessed on the NRS scale, a targeted management approach should be implemented to appropriately treat the pain. The level of pain intensity at which analgesia should be administered remains a matter of controversy in the literature. Stork and HofmannKiefer do not believe that there is a compelling indication for pain therapy preclinically at intensity of ≤3 on the NRS (Stork and Hofmann-Kiefer, 2009). Other authors (Trentzsch et al., 2011), the most recent S3 guidelines on the treatment of acute perioperative and post-traumatic pain (Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) et al., 2008), and the authors of this paper recommend administering non-opioid analgesic agents at a pain intensity of NRS ≤ 3 (Trentzsch et al., 2011), and a combination of non-opioids and opioids at an intensity of

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NRS > 3 (Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) et al., 2008). After initial management of abdominal pain, repeated pain assessment will help improve and titrate pain therapy to effect (Stork and Hofmann-Kiefer, 2009). Evaluation of pain intensity should be repeated every 15–30 min, depending on the onset of effect and efficacy of the analgesic agent used. Dosing and timing of appropriate analgesics per intensity level as well as analgesia supplements based on pain characteristic (e.g., colicky abdominal pain) are illustrated in algorithmic format in Fig. 2.

3.4.3 Adjuvant measures In cases of acute abdominal pain, patient positioning that relieves tension on the abdominal wall may help reduce pain. Measurable reductions in pain can also be achieved by offering sympathy, and providing a competent, reassuring and solutionoriented presence (Hofmann-Kiefer et al., 1998; Stork and Hofmann-Kiefer, 2009). Adjuvant measures should be initiated early in the preclinical and pre-diagnostic settings to maximize benefit to the patient.

Acute abdominal pain

Pain intensity measurement and clinical assessment NRS 1–3 (mild pain)

NRS 4–5 (moderate pain)

NRS 6–7 (severe pain)

NRS ≥ 8 (extreme pain)

1 g paracetamol* i.v. as a short infusion over 15 min

1 g paracetamol* i.v. as a short infusion over 15 min

1 g paracetamol* i.v. as a short infusion over 15 min

Try: 1 g paracetamol* i.v. as a short infusion over 15 min

OR

AND 7.5 mg piritramide** i.v. as a short infusion over 15 min

OR 1 g dipyrone** i.v. as a short infusion over 15 min (preferable in colicky pain)

2.5 g dipyrone** i.v. as a short infusion over 15 min (preferable in colicky pain) Consider adding 3.75– 7.5 mg piritramide*** i.v. as a short infusion over 15 min

AND 7.5–15.0 mg piritramide i.v. as a short infusion over 15 min

OR 2.5 g dipyrone** i.v. as a short infusion over 15 min (preferable in colicky pain)

OR 2.5 g dipyrone i.v. as a short infusion over 15 min (preferable in colicky pain)

AND 7.5 mg piritramide*** i.v. as a short infusion over 15 min

AND 7.5–15 mg piritramide i.v. as a short infusion over 15 min OR Titration with repeated administration of 3.75 mg piritramide i.v. Consultation with anesthesiologist

Supplements: For colicky pain consider 20 mg butylscopolamine bromide slowly i.v. Repeat clinical examination if not possible before pain treatment Repetition of pain measurement after 15 min for pirtramide and 30 min for paracetamol and dipyrone→ Modification of pain therapy following algorithm *Paracetamol maximum daily dose: 4g **Dipyrone maximum daily dose: 5g ***Piritramide has no established maximum daily dose. Titrate analgesia per algorithm and monitor for cardiopulmonary and nausea/vomiting side effects.

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Figure 2 Algorithm for pre-diagnostic analgesia of acute abdominal pain in general adult population.

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3.5 Analgesia for acute abdominal pain in special patient populations

Acute abdominal pain therapy in emergency patients

2012). There is inadequate data on the effects on the foetus of short-term administration of opioid analgesics.

3.5.1 Pregnancy Many drugs are not approved for use in pregnant patients, not because there is evidence that they are teratogenic, but rather because of a lack of evidence that they are safe for the foetus (Østensen and Förger, 2009). Paracetamol has no known teratogenicity or embryotoxicity (Briggs, 1998), and it can be administered throughout pregnancy and breastfeeding; it is therefore the non-opioid analgesic of choice in these patients (Greenblatt and Koch-Weser, 1976; Østensen and Förger, 2009; Scialli et al., 2010). Dipyrone is currently still regarded as being contraindicated during the first trimester (gestational weeks 1–13) and third trimester (gestational weeks 27–40), but it may be administered in the second trimester (gestational weeks 14–26) (Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) et al., 2008). A recent retrospective analysis has shown that there is no risk of teratogenic effect with dipyrone during pregnancy, and that this drug is not associated with intrauterine death, premature birth or low birthweight (Da Silva Dal Pizzol et al., 2009). Ibuprofen and diclofenac can be administered in the first and second trimesters (Greenblatt and Koch-Weser, 1976; Wilffert et al., 2011), but there is a relative contraindication for them in the third trimester (Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) et al., 2008). As ibuprofen is not transferred to breast milk, it is regarded as safe during breastfeeding and is therefore the NSAID of choice in this setting (Greenblatt and Koch-Weser, 1976; Risser et al., 2009). There are no randomized controlled trials available on preoperative pain therapy to evaluate opioid analgesia for acute abdominal pain during pregnancy and breastfeeding. However, piritramide should be considered in this setting based on successful post-operative pain therapy results for these patients (Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) et al., 2008). Patients who are breastfeeding should only resume breastfeeding ≥24 h after the last dose of piritramide (Deutsche Interdisziplinäre Vereinigung für Schmerztherapie (DIVS) et al., 2008). It is important to note that opioid analgesics administered as long-term therapy and during birth can lead to withdrawal syndromes (Schaefer and WeberSchöndorfer, 2009). Sudden withdrawal of opioids that have been taken for a prolonged period during pregnancy can trigger intrauterine abstinence syndrome and neonatal abstinence syndrome (McCarthy, © 2014 European Pain Federation - EFIC®

3.5.2 Patients with opioid tolerance and/or drug dependency Patients with opioid tolerance often report severe pain perioperatively, and require more analgesics over a longer period (Rittner and Brack, 2011). All patients who become accustomed to opioids develop physical dependency and tolerance. Psychological dependence and addiction, however, usually only develop in cases of opioid abuse. Associated physical and psychological factors in opioid abuse patients may make it difficult to distinguish between pain, opioid withdrawal and psychiatric pathology. Concern over increased dependency in opioid-tolerant patients is not usually justified in the management of acute abdominal pain, and withdrawal should not be attempted perioperatively (Rittner and Brack, 2011). To avoid inadequate or inappropriate care, early interdisciplinary collaboration, and if necessary psychological or psychiatric involvement in the patient’s care, should be sought. In opioid-addicted patients, perioperative withdrawal symptoms may require treatment with L-methadone, perhaps in addition to intravenous clonidine (0.5– 2.0 μg/kg body weight per hour). Former drug addicts do not require withdrawal prophylaxis.

3.6 Ethical and medico-legal consideration in current analgesia practices In addition to the clinical benefits of appropriate analgesia, there are also ethical and legal obligations to the patient. Giesa et al. point out that failure to provide adequate pain treatment may count as failure to render assistance in an emergency (Section 323c of the German Criminal Code) (Giesa et al., 2007). In terms of professional regulations, the duty to relieve pain is stipulated in Section 1, Paragraph 2 of the professional code of conduct for physicians in Germany. It has been stated, that inadequate pain therapy due to poor training or time shortages makes the hospital trust management culpable for failure to provide an adequate organizational system (Biermann, 1999; Giesa et al., 2007).

4. Summary and recommendations In summary, our comprehensive review of the literature revealed that abdominal pain is the most frequent reason for acute pain therapy in emergency Eur J Pain •• (2014) ••–••

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departments relevant to the general surgeon. Untreated pain affects patient comfort and impairs the organism, with sometimes far-reaching and enduring negative consequences (Amoli et al., 2008). In this light, every patient should be offered adequate and timely pain therapy when indicated. Unfortunately, prevalent concerns remain over administration of analgesics fearing that they may negatively influence diagnosis and management of acute abdominal pain (LoVecchio et al., 1997; Grundmann et al., 2010). Notably, the net result is that up to three-quarters of all these patients initially have analgesics withheld from them (Jawaid et al., 2009). In contrast to these fears, several evidence-based studies (Attard et al., 1992; Pace and Burke, 1996; LoVecchio et al., 1997; Vermeulen et al., 1999; Mahadevan and Graff, 2000; Thomas et al., 2003; Gallagher et al., 2006; Amoli et al., 2008), and one Cochrane review (Manterola et al., 2011), support prompt analgesia administration prior to the aetiological diagnosis of acute abdominal pain patients. Pain therapy should, therefore, no longer be withheld from or delayed for these patients, and it should be initiated prior to diagnosis after assessment of relevant pain characteristics, by administering the most appropriate analgesic agents in a timely manner. This process includes: (1) Focused assessment of the intensity of pain with NRS (Fig. 1B). (2) Intravenous analgesia: (a) Non-opioid (dipyrone or paracetamol) for NRS ≤ 3 (b) Combination of opioids (piritramide) and non-opioids for NRS > 3 (c) Consideration of supplementing analgesia with a spasmolytic (butylscopolamine bromide) if renal or biliary colic is suspected. (3) Early initiation of adjuvant measures to promote patient comfort. (4) Repeated NRS pain intensity evaluations every 15–30 min, as well as identification and treatment of analgesic side effects and complications. These recommendations are illustrated in a clinical decision support algorithm in Fig. 2. While the algorithm applies well to the general adult population, the patient population seen in the ER for acute abdominal pain is heterogeneous and several considerations must be taken into account on their behalf. Alternative analgesic strategies should be considered for both special patient populations (as described above) and for contraindications (e.g., allergies) to the recommended analgesic agents. Further, closer monitoring should be implemented in cases of cardiovascular or pulmonary suppression attributable to either the 10 Eur J Pain •• (2014) ••–••

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underlying abdominal pathology or patient comorbidities, particularly when administering opioids.

Author contributions All authors substantially contributed to the (1) conception and design; (2) drafting and critical revising of the paper; and (3) final approved the submitted version.

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