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Analgesics Administered for Pain During Hospitalization Following Lower Extremity Fracture

A Review of the Literature

Griffioen, Mari A., PhD, RN; O'Brien, Grace

doi: 10.1097/JTN.0000000000000402

Effective treatment of acute pain during hospitalization following lower extremity fracture is critical to improve short-term patient outcomes including wound healing, stress response, hospital length of stay, and cost as well as minimizing long-term negative patient outcomes such as delayed return to work, disability, and chronic pain. As many patients report moderate to severe pain during hospitalization, identifying the analgesics that most effectively reduces pain is a priority to improve patient outcomes. The purpose of this review was to examine published studies describing patient response to analgesics administered orally (PO) or intravenously (IV) in the immediate hospitalization following lower extremity fracture. PubMed was queried for articles published through May 2017 that included information on type of study, population, fracture site, pain measurement tool, analgesic, and result. Of 514 articles found, eight met the inclusion criteria. Analgesics administered PO or IV were fentanyl, hydromorphone, morphine, remifentanil, diclofenac, ibuprofen, ketorolac, and etoricoxib. Five of the studies focused on comparisons between one or more analgesics and three studies compared an IV analgesic to a regional anesthetic agent. Two studies compared different nonsteroidal anti-inflammatory drugs (NSAIDs). Bupivacaine, lignocaine, and levobupivacaine administered as regional nerve blocks were superior to controlling pain compared with IV fentanyl and IV hydromorphone. IV morphine provided faster and better pain relief compared with IV ibuprofen. Based on the limited data available, regional nerve blocks provided superior pain relief compared with opioids, and opioids provided superior pain relief compared with NSAIDs. Different NSAIDs provided similar pain relief.

University of Delaware School of Nursing, Newark.

Correspondence: Mari A. Griffioen, PhD, RN, University of Delaware School of Nursing, 25 N. College Ave, Newark, DE 19716 (

This study was supported by a University of Delaware School of Nursing Seed Grant.

The authors would like to thank Sarah Katz for assistance in designing the search strategy for the PubMed search.

The authors declare no conflicts of interest.

Pain is a complex phenomenon with sensory and emotional components and treatment can be challenging and inadequate (Pizzo, Clark, & Pokras, 2011). For up to 60% of adult lower extremity (LE) fracture patients, analgesics administered during hospitalization do not adequately control pain (Archer, Castillo, Wegener, Abraham, & Obremskey, 2012 ; Griffioen et al., 2017). Furthermore, 30% of patients with long bone fractures do not receive any analgesics for pain while in the emergency department (Brown, Klein, Lewis, Johnston, & Cummings, 2003 ; Minick, Clark, & Dalton, 2012 ; Ware, Epps, Clark, & Chatterjee, 2012). Although acute pain serves an important protective function, and gradually resolves as the injury heals (Pizzo et al., 2011), effective treatment of pain at the time of injury is critical for patient comfort, wound healing, the body's stress response, hospital length of stay, cost, and minimizing long-term negative patient outcomes such as delayed return to work, disability, and chronic pain (Ahmadi et al., 2016 ; Rivara et al., 2008 ; Wells, Pasero, & Mccaffery, 2008).

The goal of analgesic administration at the time of acute pain is analgesia, which is defined as the absence of pain in response to stimulation, which would normally be painful (Loeser & Treede, 2008). Analgesics are in general administered based on pain intensity, which is the magnitude or strength a person assigns a painful episode and most frequently assessed using the 11-point Likert Numeric Rating Scale (The Joint Commission, 2011). The three-step analgesic ladder, created by the World Health Organization, recommends that treatment of pain starts with nonopioids such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAID) for mild pain (1–3), followed by acetaminophen/opioid combinations for moderate pain (4–6), and opioids for severe pain (7–10) (Bergman, 2007 ; Blondell, Azadfard, & Wisniewski, 2013 ; Pasero & McCaffery, 2011 ; Vargas-Schaffer, 2010). In addition, adjuvant analgesics, medications that have a primary indication other than that for pain, but have been shown to have analgesic effects in some pain conditions can be administered (Pasero & McCaffery, 2011). Some of these adjuvant analgesics are antidepressants, corticosteroids, and alpha-adrenergic agonists (Pasero & McCaffery, 2011).

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In general, intravenous (IV) fentanyl, hydromorphone, and morphine are the preferred analgesics for treating acute pain from a variety causes immediately upon a patient's arrival in the hospital (Ahmadi et al., 2016 ; MacKenzie, Zed, & Ensom, 2016). However, which analgesics are most effective in decreasing the pain score for adult patients with LE fractures have not been reported. The purpose of this review was to examine published studies describing patient response to analgesics administered orally (PO) or IV in the immediate hospitalization following LE fractures.

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Design and Sample

PubMed was queried for articles published through May 2017 that included information on type of study, population, fracture site, pain measurement tool, analgesic, and results. The search strategy included MeSH and text words. The following terms were included: acute pain, fractures, bone, injuries, trauma, pharmaceutical preparations, medication, and analgesics. All LE fracture sites except for hip fractures were included in the review. The search strategy was limited to articles in English, humans, adults, and analgesics administered IV or PO. Articles were included if they described experimental, quasiexperimental, correlational, or descriptive studies. In contrast, case studies, practice guidelines, review articles, and letters to the editor, as well as analgesics administered during anesthesia, were excluded. The authors reviewed titles, abstracts, and articles for eligibility. Articles that were included were reviewed in detail during face-to-face meetings.

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Of 540 articles found in PubMed, 72 were duplicates, 351 were excluded at title level, 80 were excluded at abstract level, and 29 were excluded at the full article review, leaving eight articles that met the inclusion criteria (Figure 1). Reasons for exclusion included the following: no LE fracture, hip fracture, case report, no fracture, LE fractures and additional fracture sites (vertebral, rib, upper extremity, facial), fracture related to underlying disease process (cancer, osteoporosis, arthritis), no PO or IV analgesics administered, treatment administered outside the hospital, no pain measurement tool, and no analgesic comparisons.

Figure 1

Figure 1

The studies providing information on analgesics for LE fractures are shown in Table 1. Analgesics administered PO or IV in the eight studies include opioids, NSAIDs, and cox-2 inhibitors. Five of the studies focused on comparisons between one or more analgesics, and three of the studies compared an IV opioid analgesic to a regional anesthetic agent. Six studies were randomized controlled clinical trials, one was a prospective cohort study, and one was a retrospective chart review. The smallest sample size was 14 and the largest was 293. Although all but one of the studies reported the study population by gender, all the results were reported by merging both genders. The mean age for the study populations ranged from 26–62 years, with most in the 43- to 45-year range.



Morphine IV was found to provide faster pain relief compared with ibuprofen IV (Pan, Qi, Wen, & Chen, 2016) and just as effective as continuous regional nerve block using levobupivacaine when administered via patient-controlled analgesia (Luiten et al., 2014). Remifentanil, a short-acting synthetic opioid, combined with a higher dose of ketamine provided more pain relief compared with lower doses of ketamine during the first 24-hr following surgery (Deng, Zheng, Wang, Tian, & Zhang, 2009). Regional nerve blocks using bupivacaine and lignocaine were more effective in providing pain relief compared with fentanyl and hydromorphone administered IV (Mutty, Jensen, Manka, Anders, & Bone, 2007 ; Ranjit & Pradhan, 2016). Diclofenac PO and ketorolac PO were as effective as etoricoxib PO in providing pain relief (Ortiz et al., 2010). Furthermore, there was no difference in pain relief between diclofenac PO and diclofenac PO administered with B vitamins thiamine, pyridoxine, and cyanocobalamin (Garza et al., 2008).

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Regional nerve blocks were superior to controlling pain compared with IV fentanyl and IV hydromorphone. IV morphine provided faster and better pain relief compared with IV ibuprofen in this review. Peripheral nerve blocks are effective in controlling pain, as they block the transmission of pain signals by targeting a specific nerve or nerve plexus (Pasero & McCaffery, 2011, p. 696). However, their use is limited, as they have to be administered by a trained health care provider as an injection, their effect is only temporary, and they can only be used for brief periods (Pasero & McCaffery, 2011, p. 696). In addition, nerve blocks have not shown to decrease opioid consumption in hip or ankle fracture patients during hospitalization (Chaudet et al., 2016 ; Goldstein, Park, Jain, & Tejwani, 2015).

Opioids, which can be administered either IV or PO, have a more general effect by binding to the μ-opioid receptors in the central nervous system and peripheral tissues (Pathan & Williams, 2012). Analgesia ensues as the descending inhibitory pain pathway is stimulated and the transmission of pain from peripheral nociceptors is decreased (Pathan & Williams, 2012). Since opioids have a rapid onset and short duration, they are preferred for treating acute pain (MacKenzie et al., 2016). Fentanyl has the fastest onset within 2–5 min, followed by hydromorphone at 5–15 min, and morphine within 5–10 min (Table 2) (Ahmadi et al., 2016 ; MacKenzie et al., 2016 ; Pain Assessment and Management Initiative, 2016). Nevertheless, as opioids exert a central nervous effect, side effects such as respiratory depression, hypotension, nausea, constipation, and pruritus limit their use (Pathan & Williams, 2012).



Although we were unable to find studies that compared the effectiveness or efficacy of morphine versus fentanyl or hydromorphone in LE fracture patients, studies examining pain in any traumatic injury have reported that IV morphine and IV fentanyl produce similar levels of analgesia, with fentanyl providing faster relief (MacKenzie et al., 2016 ; Wenderoth, Kaneda, Amini, Amini, & Patanwala, 2013). IV hydromorphone on the other hand has been found to produce greater pain relief compared with IV morphine (Chang et al., 2006). Combining opioids with nonopioids has shown that they might provide better pain relief compared with administering opioids alone (Buccelletti et al., 2014 ; Zare et al., 2014). In addition, administering opioids by routes other than PO and IV such as, in a fentanyl patch, together with a femoral nerve block has had good results in patients undergoing ankle and foot surgeries (Song, Kang, Hwang, Hwang, & Shin, 2016).

One study compared NSAIDs with another NSAID and a cox-2 inhibitor and did not find significant differences (Ortiz et al., 2010). NSAIDs inhibit prostaglandin production, which mediate inflammation; this in turn influences the balance of bone formation and resorption (McQuay & Moore, 2006, p. 475). Therefore, NSAIDs are not routinely administered for fracture patients.

A limitation found in the review of this literature includes that, although the studies provided information about analgesics administered for LE fractures, the sample sizes were small. Only two studies (Helmerhorst, Lindenhovius, Vrahas, Ring, & Kloen, 2012 ; Pan et al., 2016) conducted a priori power analysis for sample size. Another limitation is that the analgesics in the studies do not reflect current clinical practice guidelines, where hydromorphone, fentanyl, and oxycodone are most commonly administered (MacKenzie et al., 2016).

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Based on the limited data available, regional nerve blocks provided superior pain relief compared with opioids, and opioids provide superior pain relief compared with NSAIDs. Different NSAIDs provided similar pain relief. A future prospective clinical study collecting data on analgesics currently administered for pain would be helpful in determining the most effective analgesics.

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  • Local nerve blocks were superior to controlling pain compared with IV opioids (fentanyl and hydromorphone). Peripheral nerve blocks target a specific nerve or nerve plexus and block the transmission of pain. Opioids exert effect on the central nervous system and peripheral tissue and decrease the transmission of pain.
  • Opioids such as IV morphine provided faster and better pain relief compared with IV NSAIDs.
  • None of the studies compared the effectiveness of the most frequently administered analgesics against each other (fentanyl, hydromorphone, morphine), and most of the studies did not conduct a power analysis to determine whether they were adequately powered to detect clinically significant differences.
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Analgesic; Lower extremity fracture; Pain

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