Introduction

The prevalence of pain among emergency department (ED) patients is as high as 78 %, and among those with pain, underlying chronic pain conditions are present in 40 % [1, 2, 3••, 4]. Although arriving at a diagnosis and choosing the appropriate therapy to treat underlying conditions safely are the principal goals for physicians, patient in pain wants rapid and effective pain treatment. The safe and effective treatment of acute pain is a complex and challenging area for clinicians. The effective treatment of pain is associated with both a patient’s outcome and their satisfaction with their emergency care [5]. There are a wide variety of effective medicines to treat pain effectively; however, all pain medications have the potential for serious adverse events. In the United States, between 2000 and 2014, deaths related to the use of prescription opioids increased from 1.5 to 5.9 per 100,000 people, and ED visits related to the abuse and misuse of opioids have continued to increase [6••, 7–9].

Opioid analgesics have been the center of acute pain treatment throughout the history of modern medicine, and are commonly used for moderate to severe pain. Although opioids do not exhibit a ceiling effect to their analgesic effects, their use is often limited by their adverse effects. Relative to equianalgesic doses of many nonopioid analgesics, they are relatively safe in the acute setting and are tolerated by most patients. As the dose and the duration of treatment increases, however, the adverse events of opioids increase drastically. With adequate attention to the risks and adverse effects, opioids can be titrated to a dose that will treat almost any degree of pain safely. As the duration of the use of opioids increases, they continue to be easy to use, but their effectiveness and diminish, to the point that it is not clear they are safe or effective for chronic pain.

In this article, we will use three cases describing common clinical scenarios to discuss the safe and appropriate use of opioid analgesics. We will use the term “opioid analgesics” to generally refer to any medication that has either agonistic or antagonistic activity at opioid receptors. This review is not intended to be comprehensive; there are many indications and approaches to the use of opiod analgesics; however, we will attempt to cover some of the most common opioids and issues that arise with their use.

Opioid analgesics may be administered by a variety of routes; however, the vast majority of medications are administered by the oral or parenteral routes [10]. Oral therapies are most commonly employed, as they are convenient and inexpensive for patients who can tolerate oral intake. For most common oral opioids, the onset is within 20–30 min, but it is variable, making titration difficult for acute painful conditions. When pain is severe, analgesics must be given immediately and titrated to effect, generally by parenteral routes, either intramuscular (IM) or intravenous (IV). Intramuscular injections are painful, do not allow for rapid titration, have unpredictable absorption, and result in a slower onset of drug action. IV opioids have a predictable onset after administration, allowing more rapid and accurate titration of the appropriate dose. Unless intravenous access cannot be obtained, IM opioids should be avoided.

Case 1: Acute Musculoskeletal Injury

A 75-year-old woman with a history of hypertension and COPD presents to the emergency department after missing a step and twisting her ankle. The patient describes hearing a cracking sound and is unable to bear weight. Examination reveals a swollen right ankle with intact pedal pulses, and is otherwise notable only for an oxygen saturation of 93 %. X-ray of the right ankles reveals a moderately displaced bimalleolar fracture. As you make preparations to treat the patient, you consider how to treat her pain.

Dosing and Safety Considerations of Opioids

Opioids are the mainstay of ED therapy for moderate to severe pain, and morphine is the standard of comparison for all of the opioids. If it is contraindicated because of an allergy or adverse effect, hydromorphone or fentanyl can be substituted. These opioids can be rapidly titrated intravenously to control severe pain, allowing the establishment of a stable regimen that can be oral. Intravenous morphine is the standard of treatment for severe pain in the ED. Morphine 0.1 mg/kg bolus has been found to be safe but not usually adequate to effective pain relief [11•]. Repeat boluses of 0.05 mg/kg every 15 min until pain relief represents a safe incremental strategy. When administered IV, morphine reaches a peak of action in 15–20 min with a half-life of 1.5–2 h in healthy, young adults, and slightly longer in the elderly. Its clinical analgesic effect lasts 3–4 h, and it has a gradual offset due to its active metabolites.

Hydromorphone is a semisynthetic derivative of morphine that is a potent analgesic agent, increasingly used in the management of acute pain in the ED [12, 13]. Hydromorphone is approximately seven times more potent than morphine with a similar duration of action. The administration of 7 mg of morphine is roughly the analgesic equivalent of 1 mg of hydromorphone. It is important to avoid excessive doses of hydromorphone given the similarity of morphine and hydromorphone other than their different doses. Pruritus, nausea, vomiting, and the accumulation of active metabolites occur less frequently with hydromorphone than with morphine at equianalgesic doses. Hydromorphone is primarily conjugated in the liver to an inactive metabolite, and as a result, is better tolerated than morphine, particularly in elderly patients and those with hepatic impairment. Patients allergic to morphine do not consistently have cross-reactivity with hydromorphone.

Use of Opioids in Acute Musculoskeletal Trauma

Due to her age and underlying risk for adverse effects from accumulating active morphine metabolites, this patient was given 0.015 mg/kg of hydromorphone, followed by repeat doses of 0.007 mg/kg every 5 min until her pain was relieved. This provided her with pain relief that continued for 3 h, at which time she was given a repeat bolus with continuing pain relief. This method of treatment results in an effective pain treatment which, due to the overlapping effect of the boluses and their gradual offset, does not have gaps in analgesia and maintains a stable analgesic effect during the acute phase of an injury.

Safety Considerations for Opioids

Opioids have predictable and dose dependent adverse effects that tend to be more pronounced in opioid naïve patients. The most common adverse event is nausea, which is seen in up to 60 % of patients with a single dose. This typically can be managed with the coadministration of an antiemetic. While this can be easily accomplished in the ED, this can be a significant limitation for outpatient therapy. Another common side effect of opioids is pruritus and urticaria. Opioids cause mast cell destabilization, and this does not represent an allergic reaction, but rather is related to the number of mast cells in a patient and the plasma concentration of the opioid. This can be managed with the coadministration of antihistamines. Another common side effect seen with opioids is constipation, which should be treated with stool softeners and bulk agents, and should be considered in any patient requiring more than one day of opioid therapy or at risk of constipation.

As the dose of opioid increases, respiratory depression, somnolence, and confusion become predominant adverse effects. These effects are generally seen at doses higher than the equivalent of 0.1 mg/kg of morphine. At early levels, this adverse effect can require painful stimulation to induce ventilation, and which requires the discontinuation of further doses of opioid until they are resolved, and the addition of interactive bedside monitoring and stimulation to induce adequate ventilation when necessary. As this effect becomes more severe, patients can require ventilator support and intubation for airway protection.

Case 2: Acute Abdominal Pain

A 45-year-old woman with a history of hypertension and diabetes presents to the emergency department with acute severe abdominal pain. Her pain started 12 h before her presentation, and has steadily gotten worse. She has nausea and has vomited twice, and any movement causes sharp pain in her abdomen. On exam, she has diffuse tenderness across her abdomen, without guarding or rebound. Her vital signs are HR 113, BP 120/90, t 37.9, and her history, exam, and evaluation are otherwise unremarkable. She has not taken anything for the pain. You decide to do an abdominal CT scan to determine the source of her severe pain, and consider how to treat her pain while she is being evaluated.

Safety and Efficacy of Short Acting Opioids for Abdominal Pain

This patient in this vignette has nonspecific abdominal pain that is concerning for a serious underlying cause. Patients such as this have a broad differential diagnosis, with many etiologies that require rapid and specific diagnosis, such as peritonitis or ischemic bowel. In the case of acute abdominal pain, for which surgical dogma historically discouraged adequate analgesia in order to avoid a missed or delayed diagnosis, a large series of studies report no deleterious effect of intravenous opioid therapy on the ability to make appropriate diagnoses [14–17]. Doses less than the analgesic equivalent of 0.1 mg/kg of morphine do not appear to change physical exam findings, and that even larger doses of opioids do not typically alter the time to diagnosis in abdominal pain [17]. However, the progression of a patient’s pain, and its response to treatments or observation can be complicated by opioid pain treatment.

The synthetic short acting opioid fentanyl has been shown to have a rapid onset of 1–2 min, and a rapid offset, with a clinical effect lasting 45 min. This gives fentanyl the advantage of being easily quickly titrated and relatively short acting. The short duration of action for fentanyl makes it ideal for use in patients who require serial examinations. This allows the effective treatment of a patient’s pain, followed by a reassessment 45 min later after the offset of the medication, at which time it can be repeated as necessary. This pulsed therapy with gaps in pain treatment does not represent the optimal treatment of pain, but represents a safe and effective compromise for patients in which the progression of their pain by report and exam is important to the safe treatment of the patient’s underlying condition. Conditions where such an approach is effective include patients with multiple trauma, head injuries, chest pain, and in patients at risk of developing hemodynamic instability.

Dosing and Safety Considerations for Fentanyl

In this patient, fentanyl was chosen as the initial pharmacologic treatment given the need for ongoing assessments to accurately diagnose the patient’s underlying condition. Fentanyl is metabolized into inactive metabolites, making accumulation and toxicity unlikely during acute therapy. Fentanyl can be started at 1 ug/kg IV with repeat doses every 1–2 min of 0.5 ug/kg until the pain is relieved. Fentanyl causes less histamine release than morphine, and is associated with fewer adverse effects at an equianalgesic dose. Fentanyl is more frequently associated with respiratory depression than morphine; however, patients receiving fentanyl should be monitored with direct observation, supplemented by pulse oximetry. High or repeated fentanyl doses may produce muscle rigidity. This side effect, “rigid chest syndrome” may be so severe that it interferes with respiration, but usually occurs with doses greater than 15 μg/kg, making it rare during acute pain treatment.

Case 3: Post Procedure Pain

A 53-year-old man presents to the ED with a thrombosed external hemorrhoid. After examination, you locally anesthetize the hemorrhoid and perform and excision. The patient tolerates the procedure well, and you now consider how to treat his pain as the local anesthesia wears off.

Oxycodone

Oxycodone is a strong opioid agonist that is highly bioavailable in an oral form. Oxycodone is widely sold in combination with acetaminophen as well as by itself, and is also available in long-acting PO formulations. Oxycodone bioavailability is much higher than other opioids, and it is quickly and efficiently absorbed, which may be a causative factor in its high abuse potential. IV oxycodone is equianalgesic to IV morphine, and due to its high bioavailability, a 15-mg oral oxycodone dose has similar clinical effect to 10 mg of IV morphine. The onset of action of PO oxycodone is approximately 20–30 min.

Oxycodone undergoes hepatic metabolism into oxymorphone, a strong opioid agonist that accounts for its analgesic effects. Approximately 10 % of patients do not metabolize oxycodone well and are unable to generate oxymorphone. This defect in metabolism renders these patients unable to achieve clinically meaningful pain relief with typical dosing strategies and may require very large doses to achieve analgesia. This effect can also be caused by agents that compete with oxycodone’s metabolism, such as neuroleptics, tricyclic antidepressants, and selective serotonin reuptake inhibitors. Cases of serotonin syndrome are reported when serotonin reuptake inhibitors and oxycodone are given together, likely due to this metabolic interaction.

The patient in this vignette was treated with oxycodone 10 mg PO, with adequate relief of pain, and was sent home with a 3-day supply of 5 mg tablets to be taken 1–2 every 4–6 h as need for pain. This dose (very close to 0.1 mg/kg morphine equivalent in most patients), when used for less than 5 days, is not associated with medication tolerance or withdrawal symptoms. After a patient has been treated for more than 5 days with an opioid, tolerance and withdrawal must be accounted for, and patients will require gradual tapering of the medication as their pain resolves or they transition to chronic pain therapy.

Other Oral Agents for the Treatment of Acute Pain

Hydrocodone is another opioid frequently used orally, it is metabolized in the liver to hydromorphone. Hydrocodone combinations are less effective than oxycodone–acetaminophen combinations, but are not always cross reactive in patients allergic to oxycodone. The adverse effects of hydrocodone are similar to equianalgesic doses of other opioids. Codeine is also commonly prescribed oral opioid, usually in combination with acetaminophen. Codeine is a weak opioid receptor agonist and has little role in the modern treatment of pain.

Tramadol is a synthetic oral analgesic that is a weak mu agonist with some serotonin and norepinephrine reuptake qualities. Its analgesic properties are thought to be primarily due to mu receptor agonism, similar to low dose opioids. Tramadol-induced analgesia is only partially reversed by naloxone, suggesting other properties play a role in its analgesic effects. Tramadol has not been associated with physiologic dependence or opioid tolerance, although it has been associated with abuse. This makes it a preferable analgesic in some cases requiring oral opioids for prolonged periods. Compared with traditional opioids, low dose tramadol has a more favorable side effect profile and may present a lower risk of addiction with chronic use. The most common tramadol side effects are nausea, vomiting, dizziness, orthostatic hypotension, and sedation. These side effects are seen in as many as 17 % of patients using the drug at low doses. At increasing doses, the adverse effects become more pronounced, limiting its use to low doses and effectively creating a therapeutic ceiling to its clinical use. Tramadol 37.5 mg appears to have similar efficacy to hydrocodone 5 mg.

When are Opioids Not Indicated?

Opioids are safe and effective for the treatment of acute pain when used carefully. As the duration of the treatment increases, their safety and effectiveness decreases. In general, a patient that requires regular opioid treatment for more than 5 days will require dose tapering to avoid withdrawal symptoms. Opioids are generally not considered safe for the treatment of mild pain, and their use for chronic pain is controversial. In addition, they are not considered effective management for primary headache syndromes due to their association with rebound headaches.

Conclusion

Opioid medications represent a safe and effective approach to the treatment of acute pain. Their safe use requires monitoring for and treatment of their adverse effects. The best approach for using opioids is to select the opioid with the onset, duration, and adverse effects that best suit a patient’s condition and pain, titrate it to adequate pain relief, continue to the medication at this level to treat the pain, and develop a plan to discontinue the medication safely.