November 2018 FAQs

What are important considerations for using cannabidiol for the treatment of pediatric seizures?

Background

Seizures are the result of excessive abnormal neuronal activity, and can present with a variety of  symptoms and severity, ranging from staring to jerking to prolonged convulsions and status epilepticus.^1-2 It is estimated that about 4 to 10% of children will experience a seizure in their lifetime, and about 30% of them progress to an epilepsy disorder. While seizures may be caused by fever, infection, or trauma, they can also be caused by several syndromes that affect primarily children. Lennox-Gastaut syndrome is a severe epileptic encephalopathy that causes multiple types of seizures and is associated with poor developmental, cognitive, and behavioral outcomes.³ It affects about 5 to 10% of children with seizures, and the majority of patients continue having seizures as adults. Dravet syndrome (formerly known as severe myoclonic epilepsy of infancy) is another rare epileptic encephalopathy resulting in multiple seizure types.⁴ Although the incidence of Dravet syndrome is unclear, current literature suggests that it affects about 1 in 40,000 to 1 in 20,000 infants, and it is also associated with high morbidity and poor long-term neurologic outcomes.

Seizures as a result of such syndromes are usually refractory and require multiple antiepileptic drugs to manage. The determination of an antiepileptic drug regimen for pediatric patients with seizures is beyond the scope of this article, but levetiracetam, lamotrigine, valproic acid, topiramate, clobazam, and rufinamide have been used.¹ The remainder of this article will discuss a new drug, cannabidiol (Epidiolex), which was approved by the Food and Drug Administration (FDA) in June 2018 with orphan drug status for the treatment of seizures associated with Lennox-Gastaut or Dravet syndrome in patients 2 years and older.⁵

Cannabis Derivatives

Major cannabinoid derivatives from the cannabis plant, Cannabis sativa, include tetrahydrocannabinol (THC) and cannabidiol (CBD).⁶ THC is the primary psychoactive component that is commonly referred to as marijuana, and its effects on pain, appetite, and mentation are considered to be due to agonist activity on the CB₁ and CB₂ endocannabinoid receptors in the brain.^6-7 Dronabinol, a synthetic THC, also has activity on cannabinoid receptors in neural tissues, and is FDA-approved as a Schedule III controlled substance for the treatment of chemotherapy-associated nausea and vomiting not alleviated by conventional antiemetics, and for anorexia with weight loss in AIDS patients.⁸

Cannabidiol

CBD, unlike THC, does not appear to act directly on the endocannabinoid receptors and may instead be an allosteric modulator of CB₁ receptors.⁵ Additionally, CBD may have effects on non-cannabinoid receptors, leading to anticonvulsant, antipsychotic, and anti-inflammatory properties.⁶ Although it still has psychotropic effects, it is speculated that these pharmacologic  differences may be why CBD has fewer intoxicating effects than THC, such as cravings and compulsiveness associated with addiction.^6,7

In the past few years, after many anecdotal reports suggesting its anticonvulsant activity, CBD was studied in controlled settings to assess the efficacy and safety in patients with uncontrolled seizures. Table 1 summarizes select evidence for the use of CBD resulting in its approval by the FDA.

Table 1. Evidence for the safety and efficacy of cannabidiol.^9-11

Based on these trials, CBD is FDA-approved for the treatment of seizures in patients with Dravet syndrome and Lennox-Gastaut syndrome in patients 2 years and older.⁵ The recommended initial oral dose is 2.5 mg/kg twice daily (5 mg/kg/day), with usual maintenance doses at 5 mg/kg twice daily (10 mg/kg/day), and a maximum dose of 10 mg/kg twice daily (20 mg/kg/day). Adverse effects of CBD include somnolence, decreased appetite, diarrhea, fatigue, lethargy, sleep disorder, pyrexia, and infections.^5,9-11 Hepatotoxicity (elevated serum transaminases and total bilirubin) is also possible, and there are recommendations for dose adjustment in hepatic impairment as well as monitoring of serum transaminases and bilirubin at baseline, 1, 3, and 6 months, and as clinically indicated thereafter.⁵

Implications for Clinical Practice

The approval of Epidiolex in the US has garnered attention for a variety of reasons: it is the first natural cannabinoid product to be approved by the FDA; it offers treatment specifically for Dravet syndrome and Lennox-Gastaut syndrome, both of which have devastating neurologic outcomes; and it can be used in pediatric patients as young as 2 years old. Despite these accolades, CBD will undoubtedly have challenges healthcare providers will need to navigate.

CBD in Pediatric Patients

Unlike in many clinical drug investigations, pediatric patients were included by design into the studies on CBD, particularly because the treatment-resistant epileptic syndromes occur primarily in children and carry forward into adulthood. As such, CBD is expected to have a high proportion of use in pediatric patients. From a drug administration perspective, it is relatively uncomplicated to give CBD to children, because it is readily available as an oral solution with a concentration of 100 mg/mL, although studies did find the taste to be unpalatable compared to placebo.^5,10

The more concerning aspect of CBD in children is the lack of data on long-term adverse effects. While some consequences of reported adverse effects may be predictable, such as decreased appetite resulting in poor weight gain and growth; others, such as impact on neurodevelopment, are less clear. The endocannabinoid system is involved in early and adolescent cortical development, progenitor cell regulation, and neural differentiation, migration and survival.¹³ Exposure to CBD could potentially have a negative impact on these processes, and there is currently insufficient evidence to show changes one way or the other.

Drug Interactions

Given its role in Dravet syndrome and Lennox-Gastaut syndrome and the context in which it was studied as an add-on agent to a baseline antiepileptic drug regimen, CBD has the potential for drug interactions, particularly with other antiepileptic drugs. Patients in the clinical trials were also taking at least one of the following antiepileptic agents: clobazam, valproate, stiripentol, levetiracetam, topiramate, lamotrigine, or rufinamide.^10,11 In the clinical trials, concomitant CBD use with clobazam possibly resulted in better seizure control, but also increased somnolence.^9,11 The drug interaction was further evaluated in pharmacokinetic studies and showed that clobazam had increased serum concentrations when given with CBD.¹⁴ Another significant drug interaction exists between CBD and valproate, in which concomitant use increases the incidence of elevated liver function tests and hepatotoxicity. An open-label pharmacokinetic study confirmed these interactions, and additionally showed increases in serum concentrations of rufinamide, topiramate, zonisamide, and eslicarbazepine, suggesting that patients taking combinations of antiepileptic drugs be routinely monitored for serum concentration elevations and/or have doses of the respective agents adjusted appropriately. Aside from antiepileptic agents, CBD may also have interactions related to inhibition and induction of metabolic enzyme activity, including CYP3A4 and CYP2C19, among others.⁵ Pharmacists will have an important role in assessing drug regimens for drug interactions and assisting with their management.

Legal Status

In September 2018, CBD was determined to be a Schedule V controlled substance by the Drug Enforcement Agency (DEA), indicating that it has low potential for both abuse and dependency.⁵ This is in stark contrast to its previous categorization as a Schedule I controlled substance. Cannabis and its derivatives are Schedule I controlled substances under US federal law, meaning that they have no medical use, high potential for abuse, and lack of accepted safety under medical supervision, and by definition CBD as a derivative was formerly considered a Schedule I controlled substance.¹² This highlights that the definitions of the cannabis (hemp) plant, its parts, and its derivatives are not explicit in the Controlled Substances Act, and exemptions to the definition make recognizing the legal status of CBD difficult. However, many states have enacted laws to allow the use of medical marijuana as well as products high in CBD and low in THC, and the extraction of cannabinoids from the cannabis plant and distribution to patients are tolerated without federal prosecution.^7,12 But overall, the legality of such products for their pharmacological purposes is oftentimes confusing, and as CBD comes to market in the near future, it remains to be seen how its scheduling will affect its prescribing and use.

Conclusion

Cannabidiol is the first natural cannabinoid derivative to be approved for use by FDA. It has the potential to play an important role in the treatment of seizures caused by Dravet syndrome and Lennox-Gastaut syndrome, and is approved for use in patients 2 years and older. While the evidence supports its efficacy and thus far the adverse effect profile is tolerable, long-term effects, particularly in children, have not been determined. Additionally, there are implications for pharmacists regarding hepatotoxicity, many potential drug interactions, and accessibility of the drug due to its current status as a controlled substance. All of these things should be considered when incorporating CBD into the care of a patient.

References

1. Sidhu R, Valayudam K, Barnes G. Pediatric seizures. Peds in Review. 2013;34(8):333-342.
2. Agarwal M, Fox SM. Pediatric seizures. Emerg Med Clin N Am. 2013;31(3):733-754.
3. Bourgeois BFD, Douglass LM, Sankar R. Lennox-Gastaut syndrome: A consensus approach to differential diagnosis. Epilepsia. 2014;55(Suppl. 4):4-9.
4. Wu YW, Sullivan J, McDaneil SS, et al. Incidence of Dravet syndrome in a US population. Pediatrics. 2015;136(5):e1310-e1315.
5. Epidiolex [package insert]. Carlsbad, CA: Greenwich Biosciences, Inc; September 2018.
6. MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med. 2018;49:12-19.
7. Russo EB. Cannabidiol claims and misconceptions. Trends Pharmacol Sci. 2017;38(3):198-201.
8. Dronabinol [package insert]. Lake Forest, IL: Akorn Inc; 2017.
9. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15(3):270-278.
10. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. NEJM. 2017;376(21):2011-2020.
11. Devinksy O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. NEJM. 2018;378(20):1888-1897.
12. Mead A. The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law. Epilepsy Behav. 2017;70(Pt. B):288-291.
13. Schonhofen P, Bristot IJ, Crippa JA, et al. Cannabinoid-based therapies and brain development: Potential harmful effect of early modulation of the endocannabinoid system. CNS Drugs. 2018;32(8):697-712.
14. Gaston TE, Bebin EM, Cutter GR. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58(9):1586-1592.

Prepared by:

Michelle Lee, PharmD

PGY2 Pediatric Pharmacy Resident

University of Illinois at Chicago College of Pharmacy

November 2018

The information presented is current as of Oct 12, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What are the 2018 SCCM guideline recommendations for pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS)?

Background

Since 2002, the Society of Critical Care Medicine (SCCM) has provided recommendations on the management of sedation and analgesia in critically ill adults.¹ To supplement the 2013 guideline on pain, agitation/sedation, and delirium (PAD), new guidance was published in September 2018 that addresses pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS).^1,2 This article will review major medication-related recommendations from the 2018 PADIS guideline and summarize pertinent evidence related to these recommendations (including data that was published after the guideline’s December 2015 evidence review cutoff).

Guideline Features

The 2018 PADIS guideline addresses many therapeutic needs of critically ill patients and patients who were survivors of critical illness were involved throughout the guideline development process.^2,3 Both the clinical questions and the evidence review process centered on the effect of interventions that resulted in patient-centric outcomes, including post-intensive care unit (ICU) survival and recovery.³ Outcomes that were not considered important by the guideline developers (both clinicians and patients) were dropped from further review even if pertinent evidence existed. Other notable features of the guideline include the involvement of experts from Europe and Australia, full transparency with >100 supplemental tables and figures that detail each step of the process, and clear articulation of gaps in the available evidence for every topic. Although critically ill subpopulations are not directly addressed, many of the principles and recommendations apply to focused populations such as neurologic or postsurgical.

A central mission of the 2018 PADIS guideline is to provide recommendations that support implementation of the evidence-based, patient-centered, ABCDEF bundle that is endorsed by the SCCM ICU Liberation Collaborative (Figure).^2,4,5 A prospective, multicenter, cohort study of 15,226 adults in the ICU reported significant benefits of ABCDEF bundle use.⁶ Complete bundle use (every bundle element was performed on a given day) was associated with a significantly reduced hazard for several patient-centered outcomes (Table). Proportional bundle use (not every bundle element was performed every day) was significantly associated with the same outcomes (all p<0.05), suggesting a “dose-response relationship” between bundle elements and outcomes.

Figure. ABCDEF Bundle Elements.^4,5

Table. Outcomes Associated with Complete ABCDEF Bundle Use.⁶

Guideline Recommendations

Of the 37 recommendations in the 2018 PADIS guideline, only 2 are strong recommendations.^2,7 The strong recommendations are noted below and are supported by moderate to high quality evidence that applies to almost all patients.⁷ The remaining recommendations are conditional. Conditional recommendations are supported by less robust evidence and may have the potential to change based on the results of future research; these recommendations apply to most patients but should be carefully considered before routinely implementing in clinical practice. Additionally, the guideline contains 32 non-actionable, descriptive statements with conclusions garnered from the panel’s literature review.

Pain

Both pain at rest and procedure-related pain occur in critically ill patients.² For pain at rest, the guideline recommends frequent assessment of pain using either a numeric rating scale (patient-reported) or the Behavioral Pain Scale (BPS) or Critical-Care Pain Observation Tool (CPOT) in patients who cannot self-report. Analgesia in the ICU is commonly achieved with opioids; concurrent acetaminophen (intravenous [IV], oral, or rectal) is recommended for opioid-sparing effects. One of the 2 strong recommendations in the guideline is for the use of neuropathic pain medication (eg, gabapentin, pregabalin, carbamazepine) with opioids in patients with neuropathic pain. The guideline also has a recommendation for adjunctive ketamine (0.5 mg/kg bolus, then a 1 to 2 mcg/kg/min infusion) in postsurgical patients. Routine use of IV lidocaine or cyclooxygenase (COX)-1 selective nonsteroidal anti-inflammatory agents (NSAIDs) in combination with opioids is recommended against. The guideline conditionally recommends offering massage, music therapy, cold therapy (procedural pain only), and relaxation techniques (procedural pain only) for non-pharmacologic analgesia, although each of these strategies is supported by low quality evidence.

An opioid at the lowest effective dose should be used to manage procedural pain.² An NSAID (IV, oral, or rectal) can be used as an alternative to opioids for individual, infrequent procedures. Local analgesia/nitrous oxide/NSAID topical gel and inhaled volatile anesthetics are recommended against and strongly recommended against, respectively, for procedural pain.

Agitation/Sedation

The guideline contains a conditional recommendation for using an assessment-driven, protocolized, stepwise approach to managing pain and sedation in the ICU, also known as analgosedation.² Analgosedation involves either an opioid before a sedative (analgesia-first) or an opioid as a sedative (analgesia-based) to achieve sedation goals. Similar to the 2013 PAD guideline, the 2018 PADIS guideline recommends the use of light sedation in the majority of mechanically ventilated adults for the majority of the time. Light sedation is not well-defined but generally corresponds to a Richmond Agitation-Sedation Scale (RASS) score of -2 to +1. A sedative agent (eg, a benzodiazepine) may be required in addition to opioids in patients with alcohol withdrawal, status epilepticus, or paralysis with neuromuscular blocking agents. The use of physical restraints is not supported by high quality evidence and remains controversial.

Clinicians have long debated about the optimal sedative agent. The 2013 PAD guideline conditionally recommends using propofol or dexmedetomidine rather than benzodiazepines due to improved short-term outcomes.¹ When both long-term and short-term outcomes were considered in the 2018 PADIS guideline, propofol was identified as the preferred sedative after cardiac surgery (over benzodiazepines; dexmedetomidine was not evaluated in the setting of cardiac surgery), but the recommendation for all other critically ill patients remains unchanged (either propofol or dexmedetomidine rather than benzodiazepines, although propofol is preferred when deep sedation is required).² Four randomized, controlled trials that compared propofol and dexmedetomidine were reviewed but only one found a difference between these agents (decreased incidence of delirium with dexmedetomidine at 48 hours after stopping therapy).^2,8

The 2018 PADIS guideline does not comment on the appropriate duration for the dexmedetomidine infusion, which is commonly given for longer than the 24 hour maximum given in the product labeling.⁹ The guideline also does not comment on the comparative potential for hypotension with propofol and dexmedetomidine, which is a common clinical concern.²

Delirium

Based on strong evidence, risk factors for delirium in critically ill adults include modifiable factors (eg, benzodiazepine use, blood transfusion) and nonmodifiable factors (eg, age, dementia, prior coma, pre-ICU emergency surgery or trauma, and increasing Acute Physiology and Chronic Health Evaluation [APACHE] and American Society of Anesthesiology [ASA] scores).² In light of the distress that delirium can cause to the patient and family, and in light of the potential benefit, the guideline endorses regularly screening patients for delirium using a validated assessment tool such as Confusion Assessment Method for the ICU (CAM-ICU) or the Intensive Care Delirium Screening Checklist (ICDSC). Sedation and level of arousal may affect the occurrence and assessment of delirium and rapidly reversible delirium has been reported in the literature (leading to similar outcomes as patients who did not experience delirium); therefore, the guideline states that delirium assessments should be performed both before and after a spontaneous awakening trial.^2,10 Screening when patients are more wakeful may minimize the potential for false-positive assessments.

No pharmacologic agent is recommended in the 2018 PADIS guideline for routine prophylaxis or treatment of delirium due to a lack of compelling and consistent data on important patient-centered outcomes.² Although commonly used in practice, neither prospective cohort studies nor a recently-published randomized, placebo-controlled trial (MIND-USA) have identified a mortality benefit with haloperidol or atypical antipsychotics in the treatment of delirium.^{11, 12} Another randomized trial that was published in 2018 (REDUCE) found that preventative haloperidol did not improve survival compared to placebo in patients at high risk for delirium.¹³ However, the guideline acknowledges that patients who experience significant distress (eg, anxiety, fear, hallucinations, delusions, or agitated enough to cause harm to themselves or others) may benefit from short-term therapy with haloperidol or an atypical antipsychotic until the distressing symptoms resolve.² Dexmedetomidine is recommended for mechanically ventilated patients in whom delirium-related agitation is preventing weaning or extubation. Nonpharmacologic interventions to reduce modifiable risk factors for delirium and optimize sleep, mobility, hearing, and vision are recommended.

Immobility

Physical function is often neglected during an ICU stay which can lead to long-term sequelae including ICU-acquired muscle weakness as a result of prolonged bed rest.² The 2018 PADIS guideline recommends performing rehabilitation or mobilization in critically ill patients to better maintain physical function, including patients on vasopressors, continuous renal replacement therapy, mechanical ventilation, or femoral vascular access. These interventions rarely result in harm and can be optimized with pre-mobilization analgesia if needed and ensuring a low level of sedation at the time of mobilization. Mobilization should be withheld in the setting of new cardiovascular, neurologic, or respiratory instability.

Sleep

The relationship between critical illness, sedation, delirium and sleep is not well-characterized, but sleep disruption is common in ICU patients and often results in patient distress and impaired recovery.² Sleep can also be disrupted in the ICU due to potentially modifiable factors such as the environment (eg, noise, light, interruptions), strong emotions such as fear, or the experience of pain or discomfort. Risk factors for poor sleep in the ICU include poor sleep quality at home and the use of medication to assist with sleep at home; therefore, implementing sleep hygiene measures may help many critically ill patients. Noise and light reduction with eyeshades and earplugs, respectively, is recommended when tolerated by the patient. In a randomized trial these strategies increased high quality sleep as measured by polysomnography.¹⁴ Another nonpharmacologic strategy to improve sleep is the use of assist-control mechanical ventilation at night instead of pressure support ventilation.² Sleep promoting protocols may help clinicians to consider all potential interventions for each individual patient.

After considering the available evidence, no pharmacologic agent is recommended to improve sleep in critically ill patients.² Specifically, the guideline recommends not using propofol and makes no recommendation regarding dexmedetomidine or melatonin. A recent randomized trial that compared low-dose nighttime dexmedetomidine (0.2 to 0.7 mcg/kg/hour titrated to RASS goal of -1) to placebo found no difference in patient-reported sleep quality between groups but the study was likely not powered to detect a difference in this outcome.¹⁵ A more compelling finding of this study was a lower risk of delirium in the dexmedetomidine group (relative risk 0.5, 95% confidence interval 0.23 to 0.82, p=0.006).

Conclusion

The 2018 PADIS guideline is an evidence-based, patient-centered companion document to the 2013 PAD guideline.^1,2 Implementation of the 2018 recommendations and the ABCDEF bundle requires collaboration with multidisciplinary stakeholders, provider education on the experiences and priorities of patients after ICU discharge, and the resources of the organization.⁷ Clinicians are urged to stay abreast of current knowledge and to perform research and publish evidence that will narrow the knowledge gaps that currently exist in this rapidly-changing field.

References

1. Barr J, Fraser GL, Puntillo K, et al; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306.
2. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825-e873.
3. Devlin JW, Skrobik Y, Rochwerg B, et al. Methodologic innovation in creating clinical practice guidelines: insights from the 2018 Society of Critical Care Medicine pain, agitation/sedation, delirium, immobility, and sleep disruption guideline effort. Crit Care Med. 2018;46(9):1457-1463.
4. Society of Critical Care Medicine. ICU Liberation. http://www.sccm.org/ICULiberation/Home. Accessed October 24, 2018.
5. Barnes-Daly MA, Pun BT, Harmon LA, et al. Improving health care for critically ill patients using an evidence-based collaborative approach to ABCDEF bundle dissemination and implementation. Worldviews Evid Based Nurs. 2018;15(3):206-216.
6. Pun BT, Balas MC, Barnes-Daly MA, et al. Caring for critically ill patients with the ABCDEF bundle: results of the ICU Liberation Collaborative in over 15,000 adults [published online ahead of print October 18, 2018]. Crit Care Med. doi: 10.1097/CCM.0000000000003482
7. Balas MC, Weinhouse GL, Denehy L, et al. Interpreting and implementing the 2018 pain, agitation/sedation, delirium, immobility, and sleep disruption clinical practice guideline. Crit Care Med. 2018;46(9):1464-1470.
8. Jakob SM, Ruokonen E, Grounds RM, et al; Dexmedetomidine for Long-Term Sedation Investigators. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012;307(11):1151-1160.
9. Precedex [package insert]. Lake Forest, IL: Hospira, Inc: 2017.
10. Kenes MT, Stollings JL, Wang L, Girard TD, Ely EW, Pandharipande PP. Persistence of delirium after cessation of sedatives and analgesics and impact on clinical outcomes in critically ill patients. Pharmacotherapy. 2017;37(11):1357-1365.
11. Collett MO, Caballero J, Sonneville R, et al. Prevalence and risk factors related to haloperidol use for delirium in adult intensive care patients: the multinational AID-ICU inception cohort study. Intensive Care Med. 2018;44(7):1081-1089.
12. Girard TD, Exline MC, Carson SS, et al; MIND-USA Investigators. Haloperidol and ziprasidone for treatment of delirium in critical illness [published online ahead of print October 22, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1808217.
13. van den Boogaard M, Slooter AJC, Brüggemann RJM, et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: the REDUCE randomized clinical trial. JAMA. 2018;319(7):680-690.
14. Demoule A, Carreira S, Lavault S, et al. Impact of earplugs and eye mask on sleep in critically ill patients: a prospective randomized study. Crit Care. 2017;21(1):284.
15. Skrobik Y, Duprey MS, Hill NS, Devlin JW. Low-dose nocturnal dexmedetomidine prevents ICU delirium. A randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2018;197(9):1147-1156.

Prepared by:

Heather Ipema, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

November 2018

The information presented is current as of October 24, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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Is intravenous lidocaine effective for renal colic in patients with urolithiasis?

Urolithiasis refers to the presence of a stone in the kidney, bladder, ureter, or urethra.¹ Urolithiasis is quite common with 10.6% of men and 7.1% of women reporting a history of kidney stones, nearly 1 million emergency department (ED) visits annually for pain associated with urolithiasis, and an estimated lifetime prevalence of 19% in men and 9% in women.^2-4 The presenting symptoms often include hematuria, flank pain, nausea, and vomiting.¹ The pain associated with urolithiasis is referred to as renal colic and is due to obstructed urinary flow.

There are both medical and surgical treatment options for urolithiasis.¹ Pharmacologic options include medications to treat the pain as well as medications to enhance stone passage. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat renal colic, with opioid pain relievers reserved for refractory pain. Recently, there has been substantial interest in the use of intravenous (IV) lidocaine as a treatment option for pain associated with renal colic. Lidocaine is believed to be an effective analgesic because of its anti-inflammatory properties, and it has been used successfully to treat many kinds of pain includeing neuropathic pain, back pain, postoperative pain, and migraine.⁵

The Table summarizes the literature evaluating the use of IV lidocaine for renal colic.

Table. IV lidocaine for the treatment of renal colic.^6-10

Discussion

Both randomized controlled trials and observational studies support the use of IV lidocaine for the management of renal colic.^6-10 A single dose of 1.5 mg/kg appears to be the most common dose studied. Although all of the above studies mention that the lidocaine was administered IV, the specific details of administration were lacking in some studies. However, an IV bolus over 2 or 2 to 4 minutes was used in the most recent clinical trials while the largest clinical trial conducted in 2012 administered the lidocaine by slow IV injection.^6-8

A number of limitations exist with the current literature which may limit widespread use of IV lidocaine for renal colic. The 3 randomized controlled trials were conducted at single centers outside of the United States and had small sample sizes.^6-8 Although the observational studies included in the Table were conducted within the United States, these studies suffer from problems inherent with observational studies including lack of details regarding patient characteristics, drug dosing or administration, and systematic collection of adverse events.^9,10

It should also be noted that only 1 of the randomized controlled trials indicated superior pain control with IV lidocaine compared to opioid treatment.^6-8 Therefore, ED providers wishing to maximize rapid pain management may be hesitant to adopt lidocaine as either a primary, adjuvant, or rescue treatment option. The lack of NSAID comparator in these studies should also be noted, as NSAIDs are often considered first-line therapy and have been found to be as effective as opioid treatment.^1,11

Finally, if lidocaine is chosen as a treatment strategy, careful patient selection should be employed. In the clinical trials described above, patients with cardiac, hepatic, or renal disease were often excluded due to the risks of lidocaine in these patients.^6-8 In addition, the need for cardiac monitoring may be considered.

Despite the limitations of the above trials, further investigation should continue. If IV lidocaine successfully reduces the use of opioids, it may have both patient-specific as well as societal benefits. Well-designed studies comparing lidocaine to NSAIDs are needed.

References

1. Gottlieb M, Long B, Koyfman A. The evaluation and management of urolithiasis in the ED: a review of the literature. Am J Emerg Med. 2018;36(4):699-706.
2. Scales CD, Smith AC, Hanley JM, Saigal CS. Prevalence of kidney stones in the United States. Eur Urol. 2012;62(1):160-165.
3. Steinberg PL, Chang SL. Pain relief for acute urolithiasis: the case for non-steroidal anti-inflammatory drugs. Drugs. 2016;76(10):993-997.
4. Curhan GC. Nephrolithiasis. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo Dl, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20^th ed. New York, NY: McGraw-Hill; http://accesspharmacy.mhmedical.com/content.aspx?bookid=2129&sectionid=192281678. Accessed October 15, 2018.
5. Masic D, Liang E, Long C, Sterk EJ, Barbas B, Rech MA. Intravenous lidocaine for acute pain: a systematic review [published online ahead of print October 10, 2018]. Pharmacotherapy. doi: 10.1002/phar.2189.
6. Motamed H, Verki MM. Intravenous lidocaine compared to fentanyl in renal colic pain management; a randomized clinical trial. Emergency. 2017;5(1):e82.
7. Firouzian A, Alipour A, Dezfouli HR, et al. Does lidocaine as an adjuvant to morphine improve pain relief in patients presenting to the ED with acute renal colic? A double-blind, randomized controlled trial. Am J Emerg Med. 2016;34(3):443-448.
8. Soleimanpour H, Hassanzadeh K, Vaezi H, Golzari SE, Esfanjani RM, Soleimanpour M. Effectiveness of intravenous lidocaine versus intravenous morphine for patients with renal colic in the emergency department. BMC Urol. 2012;12:13.
9. Makhoul T, Kelly G, Schult RF, Acquisto NM. Intravenous lidocaine for renal colic in the emergency department [published online ahead of print August 23, 2018]. Am J Emerg Med. doi: 10.1016/j.ajem.2018.08.056.
10. Motov S, Drapkin J, Butt M, Monfort R, Likourezos A, Marshall J. Pain management of renal colic in the emergency department with intravenous lidocaine. Am J Emerg Med. 2018;36(10):1862-1864.
11. Pathan SA, Mitra B, Cameron PA. A systematic review and meta-analysis comparing the efficacy of nonsteroidal anti-inflammatory drugs, opioids, and paracetamol in the treatment of acute renal colic. Eur Urol. 2018;73(4):583-595.

Prepared by:

Courtney Krueger, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

November 2018

The information presented is current as of October 12, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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