October 2018 FAQs

What data are available to support administration of high-dose (>200 mg) iron sucrose in patients with non-dialysis-dependent chronic kidney disease?

Introduction

Iron deficiency is common among patients with chronic kidney disease (CKD), with an estimated prevalence ranging between 24 to 85%.¹  In patients with CKD, iron deficiency may occur as a result of reduced intake of iron (eg, malnutrition), decreased absorption of iron in the gastrointestinal tract, or from blood loss associated with laboratory testing.^1,2 If left untreated, iron deficiency can result in the development of chronic anemia, which causes reductions in energy and vitality, leading to an overall decline in quality of life.¹ Chronic anemia has also been shown to increase the risk of morbidity and mortality among patients with CKD.^3,4,5

Diagnosis and treatment initiation

Although the gold standard method to diagnose iron deficiency in patients is to perform an iron stain of a bone marrow aspirate, it is not commonly done due to the availability of other noninvasive and lower cost options.⁶ In the United States, iron stores are frequently estimated by measurement of serum iron, total iron-binding capacity (TIBC), and ferritin with calculation of the percent transferrin saturation (TSAT; calculated as plasma iron divided by TIBC x 100). Recommendations for initiation of iron therapy are based on both the hemoglobin level, as well as the ferritin and TSAT. International guidelines only make recommendations on supplementation of iron for patients with CKD that have been diagnosed with anemia based on their hemoglobin concentration.^7,8 In patients taking erythropoiesis-stimulating agents (ESA) for anemia, concomitant administration of iron is used both to increase the concentration of hemoglobin and to decrease the necessary ESA dose. In anemic patients with CKD (regardless of ESA status), guidelines recommend initiation of iron therapy when the TSAT is ≤30% or the ferritin is ≤500 ng/mL. Some experts recommend that non-dialysis-dependent CKD patients be treated for iron deficiency, even in the absence of diagnosed anemia, when their TSAT is ≤20% or their ferritin is ≤100 ng/mL.^1,9 

Treatment options

In patients with anemia and non-dialysis-dependent CKD, guidelines generally recommend initiation of oral iron first-line.^7,8 Oral iron does have some limitations, including a low absorption overall, which is further reduced in chronic inflammatory conditions such as CKD.¹ It is also associated with significant gastrointestinal side effects, which may lead to discontinuation.¹⁰ Intravenous (IV) iron preparations avoid the risk of gastrointestinal side effects due to their route of administration, but are associated with hypersensitivity reactions, which can sometimes be severe.¹ One study that was performed to compare the efficacy and safety of oral vs IV iron in patients with non-dialysis-dependent CKD found that IV iron was associated with a significantly increased mean hemoglobin, ferritin, and transferrin saturation, and significantly fewer treatment-related adverse events when compared with an oral preparation.¹¹ Several factors should be considered when selecting the best route of administration of iron, including severity of iron deficiency, patient response to previous trials of oral therapy, availability of venous access, potential side effects, patient compliance, and cost.⁷

Iron dextran (especially high-molecular-weight formulations, which are no longer used) is associated with a higher incidence of serious adverse effects, including anaphylaxis, compared to other agents such as ferric gluconate and iron sucrose.^2,7,8,10  Other IV iron formulations are comparable in terms of efficacy, and the choice of agent is often based on dosage/frequency, formulary considerations, and cost.^9,12 Table 1 summarizes the differences in available IV iron formulations, including indications, recommended dose, and frequency.

Table 1. IV iron products – indications, dosage and administration^9,13-17

High Dose IV Iron Sucrose

Iron sucrose is a popular choice amongst IV iron products since it is one of the most widely used and studied IV iron agents internationally, and is lower in cost than many of the other available options.¹² The recommended dosing for iron sucrose in patients with non-dialysis-dependent CKD, per the package insert, is 200 mg given either as a slow IV injection over 2 to 5 minutes or diluted in up to 100 mL of normal saline and infused over 15 minutes.¹⁷ The 200 mg dose should be given on 5 separate visits over a 14 day period, for a total dose of 1 gram. This dosing schedule is logical and convenient for patients who require regular hemodialysis, since they are already required to come to a clinic several days per week to receive dialysis. In patients with CKD that do not require dialysis, however, the requirement for frequent dosing over two weeks is inconvenient, which may lead to the selection of other, more expensive IV iron options that can be given in full in one or two doses over a short period of time. The package insert also describes limited experience with a dose of 500 mg IV iron sucrose infused over 3.5 to 4 hours on day 1 and day 14, suggesting that higher doses have been tested and found to be safe in patients with non-dialysis-dependent CKD.¹⁷ Although this dosing strategy allows for less-frequent visits, it may still be difficult for patients to coordinate attending two separate visits that are spread apart by two weeks. Therefore, a literature search was performed to determine if any evidence exists to support higher doses of IV iron sucrose in patients with non-dialysis-dependent CKD, either administered as a single infusion, or over a shorter period than the 14 days recommended in the package insert.     

Clinical Literature Summary

Table 2 summarizes the existing literature evaluating the safety and efficacy of IV iron sucrose in doses greater than 200 mg in patients with non-dialysis-dependent CKD. The literature is largely made up of observational studies with relatively small sample sizes, the majority of which were uncontrolled. The dosages of IV iron sucrose that were studied varied, with 1 study evaluating 300 mg given every other day for a total of 3 doses,²¹ another evaluating varying doses between 100 mg and 1000 mg given as a single infusion,¹⁹ a third evaluating 500 mg given as a single infusion on two consecutive days (for a total of 1000 mg),²⁰ and the last evaluating doses of 200 mg, 500 mg, 300 mg, and 400 mg given as a single infusion and tested in sequential order.¹⁸ One study investigated both safety and efficacy of the administered dose,²⁰ and the other 3 only reported safety outcomes. Only one of the four studies found a significant increase in adverse events related to higher doses (>300 mg) of iron sucrose.¹⁸ The authors of the study noted that the increase in adverse events may have been related to the short, 2-hour infusion time and suggested that the risk of adverse events might be reduced with a longer infusion time. Another study tested a 1000 mg dose of iron sucrose in 8 patients (2 pre-dialysis), given once over 6 hours, and did not report any adverse events.¹⁹ Similarly, a dose of 500 mg given once over 3 hours (either for one dose, or for two doses 1 day apart) was not found to be associated with an increased incidence of adverse events in two studies.^19,20 Blaustein and colleagues also found that a dose of 500 mg given once per day for 2 consecutive days was efficacious, and led to significant increases in both ferritin and TSAT from basline.²⁰ As expected based on the findings in higher doses, doses of 300 mg were well-tolerated.^18,21

Table 2. Studies evaluating the use of IV iron sucrose in doses >200 mg in patients with non-dialysis-dependent CKD.^18-21

Conclusion

Iron deficiency is common among patients with CKD, and can lead to development of chronic anemia if left untreated. Chronic anemia causes a reduction in overall energy and quality of life, and has been shown to increase the risk of morbidity and mortality in patients with CKD. International guidelines recommend treatment of iron deficiency in patients with anemia when the TSAT falls below 30% or the ferritin is less than 500 ng/mL. Although treatment with oral iron is preferred first-line, the route of administration should be selected based on several patient- and treatment-specific factors. Iron sucrose is an IV iron preparation that widely used and studied across the world; however, its requirement for frequent dosing over a period of 14 days may deter use in patients with non-dialysis-dependent CKD. Limited data from observational, mostly uncontrolled studies have shown that IV iron sucrose may be safe to administer in doses > 200 mg, up to 1000 mg at once, if given over an extended dosing interval up to 6 hours, without an increase in associated adverse events. The package insert further supports the safety of doses ≤500 mg given as a single infusion. Future randomized controlled trials need to be conducted to better establish the safety of this dosing strategy.

References

1. Cappellini MD, Comin-Colet J, de Francisco A, et al.; IRON CORE Group. Iron deficiency across chronic inflammatory conditions: International expert opinion on definition, diagnosis, and management. Am J Hematol. 2017;92(10):1068-1078.
2. Macdougall IC, Bircher AJ, Eckardt KU, et al.; conference participants. Iron management in chronic kidney disease: conclusions from a "kidney disease: improving global outcomes" (KDIGO) controversies conference. Kidney Int. 2016;89(1):28-39.
3. Kovesdy CP, Trivedi BK, Kalantar-Zadeh K, Anderson JE. Association of anemia with outcomes in men with moderate and severe chronic kidney disease. Kidney Int. 2006;69(3):560-564.
4. Portolés J, Gorriz JL, Rubio E, et al.; NADIR-3 Study Group. The development of anemia is associated to poor prognosis in NKF/KDOQI stage 3 chronic kidney disease. BMC Nephrol. 2013;14:2.
5. Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med. 2004;164(6):659-663.
6. Berns, JS. Diagnosis of iron deficiency in chronic kidney disease. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 13, 2018.
7. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Disease Improving Global Outcomes website. https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-Anemia-Guideline-English.pdf. Published August 2012. Accessed September 13, 2018.
8. Madore F, White CT, Foley RN, et al.; Canadian Society of Nephrology. Clinical practice guidelines for assessment and management of iron deficiency. Kidney Int Suppl. 2008;(110):S7-S11.
9. Berns, JS. Treatment of iron deficiency in nondialysis chronic kidney disease (CKD) patients. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 13, 2018.
10. Camaschella C. Iron deficiency: new insights into diagnosis and treatment. Hematology Am Soc Hematol Educ Program. 2015:8-13.
11. Qunibi WY, Martinez C, Smith M, Benjamin J, Mangione A, Roger SD. A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of non-dialysis-dependent chronic kidney disease patients. Nephrol Dial Transplant. 2011;26(5):1599-607.
12. Auerbach M, Macdougall I. The available intravenous iron formulations: History, efficacy, and toxicology. Hemodial Int. 2017;21 Suppl 1:S83-S92.
13. Injectafer [package insert]. Shirley, NY: American Regent, Inc.; 2018.
14. Ferrlecit [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2015.
15. Feraheme [package insert]. Waltham, MA: AMAG Pharmaceuticals, Inc.; 2018.
16. INFeD [package insert]. Madison, NJ: Allergan USA, Inc.; 2018
17. Venofer [package insert]. Shirley, NY: American Regent, Inc.; 2018.
18. Chandler G, Harchowal J, Macdougall IC. Intravenous iron sucrose: establishing a safe dose. Am J Kidney Dis. 2001;38(5):988-991.
19. Atalay H, Solak Y, Acar K, Govec N, Turk S. Safety profiles of total dose infusion of low-molecular-weight iron dextran and high-dose iron sucrose in renal patients. Hemodial Int. 2011;15(3):374-378.
20. Blaustein DA, Schwenk MH, Chattopadhyay J, et al. The safety and efficacy of an accelerated iron sucrose dosing regimen in patients with chronic kidney disease. Kidney Int Suppl. 2003;(87):S72-77.
21. Hollands JM, Foote EF, Rodriguez A, Rothschild J, Young S. Safety of high-dose iron sucrose infusion in hospitalized patients with chronic kidney disease. Am J Health Syst Pharm. 2006;63(8):731-734.

Prepared by:

Jessica Zacher, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

October 2018

The information presented is current as of September 13, 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 is the appropriate management of acute pain in a patient with opioid use disorder?

Introduction

Opioid use disorder (OUD) is a treatable chronic medical condition that involves the misuse of opioid substances despite patterns of physiologic and psychologic consequences.¹  Some characteristic symptoms of OUD include craving, tolerance, withdrawal effects when an opioid dose is reduced, and an inability to decrease opioid intake.  As of 2014, approximately 2.4 million Americans had a an OUD diagnosis, with about 1.9 million related to prescription opioids.²  Patients presenting with OUD may be in active addiction or remission.¹  Several pharmacologic agents, referred to as medication assisted treatment (MAT), are available to achieve and maintain remission with the goal of abstaining from opioid use.^3,4  These  options include buprenorphine, methadone, and naltrexone.³  Medication assisted treatment agents act at the opioid receptors, and activity at the receptor varies by agent.⁵  Key properties of each agent are outlined in Table 1. In general, dosing frequency for OUD is often unique from dosing for other indications, and each agent is available in several formulations. 

Table 1. Characteristics of MAT agents: buprenorphine, methadone, and naltrexone.^3,5-10

Pain management in patients with OUD can be challenging for several unique reasons.  All patients with OUD, regardless of whether they are in active addiction or remission, may experience hyperalgesia and lower tolerance to pain compared to opioid-naïve patients.^11,12  In one study, subjects with chronic pain and OUD maintained by either methadone, buprenorphine, or abstinence (n=30 per treatment group) were compared to opioid naïve subjects (n=30) using a cold water pain test.¹³ Patients with OUD had an increased sensitivity (mean time to pain=28.2 seconds) and decreased tolerance to pain (mean time to withdrawal from test=61.4 seconds) compared to opioid naïve patients (sensitivity=54.4 seconds, tolerance=137.1 seconds, p<0.001).  In a second study of hospitalized patients receiving opioids, patients with a history of OUD (n=9) reported a greater disability from pain compared to those without OUD (n=23) as assessed by the brief pain inventory measure (8.04 vs. 6.4; p=0.013).¹⁴ 

The opioid receptor activity of MAT agents may cause limitations in treating acute pain with opioid analgesics.^11,15  An example of these limitations can be seen with buprenorphine and naltrexone.  Buprenorphine has a high binding affinity for opioid receptors and acts as an agonist at the mu opioid receptor and an antagonist at the kappa opioid receptors. This high binding affinity decreases the efficacy of subsequently administered opioid pain medications.¹⁵  Likewise, naltrexone’s high binding affinity can significantly diminish the analgesic effects of opioid medications.¹¹

Additional consideration that should be taken into account when managing acute pain in patients with OUD is whether the patient is in active addiction or remission. Patients that present with active addiction and acute pain should be managed with the goal of providing adequate analgesia while preventing withdrawal.¹¹   For patients in remission, relapse may be a concern when prescribing opioid analgesics; however, uncontrolled acute pain can also play a factor in relapse risk.^16,17  Finally, because of the baseline opioid tolerance and hyperalgesia present in patients with OUD, higher opioid doses given more frequently are typically required for pain relief.¹⁸

Management of Pain in OUD

Few guidelines exist addressing acute pain management in patients with OUD.  Generally, non-opioid pharmacologic agents are recommended as first-line options whenever possible.³ The Substance Abuse and Mental Health Services Administration (SAMSHA) recommends non-pharmacologic treatment options and non-opioid analgesics for acute pain in OUD.¹⁹  Additionally, the American Society of Addiction Medicine (ASAM) recommends non-narcotic analgesics, such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), as first line agents prior to initiating opioid analgesics.³  While there is a lack of consensus on the appropriate management of acute pain with opioid analgesics in OUD, various pharmacologic strategies have been suggested to mitigate challenges, which are outlined in the following sections.

Buprenorphine

Buprenorphine’s high binding affinity to the opioid receptors may decrease efficacy of opioid analgesics.²⁰  Numerous strategies have been described to manage acute pain in patients maintained on a buprenorphine-containing regimen (eg, buprenorphine with or without naloxone).⁷  These strategies take into account certain factors such as pain severity and whether buprenorphine is continued throughout the acute pain period.

Acute pain management approaches may include discontinuing the buprenorphine-containing regimen and initiating short-acting, high potency opioids because buprenorphine may limit the analgesic properties of additional opioids.^3,11  The decision to discontinue buprenorphine-containing regimens should be individualized, as there is a general lack of strong evidence for acute pain management in patients maintained on buprenorphine.^7,21  The blocking effects of buprenorphine diminish over 24-72 hours.¹¹  Analgesic effects of opioids may be reduced during this initial discontinuation period, requiring higher doses of opioids prior to full buprenorphine elimination. Patients should be re-evaluated frequently and monitored for overdose during this time period.  If buprenorphine is discontinued in anticipation of acute pain (eg, a pre-planned procedure), it is recommended to transition to a full opioid agonist, such as a short-acting opioid or methadone 30-40 mg daily, beginning 24 hours to 5 days prior to surgery.^15,21,22 

When the decision is made to continue buprenorphine, the use of short-acting opioids is recommended for pain control.^7,11,15  The high binding affinity of buprenorphine hinders binding of subsequently administered opioids; therefore, opioids with a high affinity to the µ receptor, such as fentanyl and hydromorphone, should be selected.²⁰  Caution should be taken in all patients receiving both buprenorphine and opioid agonists, as buprenorphine can spontaneously dissociate from µ receptors, leading to overdose.¹⁸ 

In addition to the above management strategies, ASAM suggests the option of temporarily increasing the dose of buprenorphine for mild acute pain.³  This strategy is based on buprenorphine’s partial agonist effects at the µ opioid receptor, which may provide analgesic effects.¹⁵  To date, optimal dosing of buprenorphine for acute pain is not well documented; however, it may be three to four times per day (every six to eight hours) as buprenorphine’s duration of analgesic effects is shorter than its effects for withdrawal.^7,15,20  Additionally, a ceiling effect may occur at a dose of 32 mg/day, as a result of buprenorphine’s partial-antagonist properties.^7,15 

Buprenorphine Case Reports/Series

Several case reports have demonstrated safe and effective pain management following discontinuation of a buprenorphine-containing regimen.  One case report describes a 50 year old male maintained on buprenorphine/naloxone for chronic pain and opioid dependence with McArdle’s disease and acute compartment syndrome.²³ Buprenorphine/naloxone was discontinued on admission and hydromorphone patient-controlled analgesia (PCA) was initiated following surgical fasciotomy.  By post-operative day 2, his pain was adequately controlled (3/10) with a hydromorphone PCA.  An additional case report describes a 37 year old woman maintained on buprenorphine for chronic pain who underwent 2 separate urogynecologic procedures.²²  During the first procedure, she continued buprenorphine post-operatively and had inadequate pain control.  For her second procedure, buprenorphine was discontinued 5 days prior to surgery and oral hydromorphone was initiated to maintain baseline opioid requirements.  Following the procedure, high dose hydromorphone was utilized for pain control, and her pre-surgery hydromorphone dose was resumed on post-operative day one.  While this case report displays the potential impact of discontinuing buprenorphine-containing regimens on pain management, it should be noted that this patient did not have a history of OUD.

Several case studies have shown successful pain management with short-acting opioids in addition to buprenorphine.  One case report describes a 53 year old man maintained on buprenorphine three times daily for chronic pain who underwent a total knee arthroplasty.²⁴  His postoperative pain was adequately managed on buprenorphine 8 mg three times daily and a hydromorphone PCA for 48 hours followed by oral hydromorphone 10 mg and acetaminophen 325 mg as directed. Two years after his initial procedure, the patient underwent a contralateral total knee arthroplasty, but was no longer maintained on buprenorphine.  His pain was poorly controlled despite use of hydromorphone PCA, suggesting that pain can be adequately controlled with buprenorphine and opioids.  A second case series discussed 4 patients who remained on buprenorphine during and after obstetrical surgery.²⁵ A multimodal pain management approach was utilized consisting of NSAIDs, local anesthetics, acetaminophen, and in one patient, a hydromorphone PCA.  In the patient who received the hydromorphone PCA, significant pain relief was achieved following initiation.

The strategy of utilizing a buprenorphine-containing regimen alone for pain management was demonstrated by 1 low-quality case report.²⁶  In this report, a 32 year old woman maintained on buprenorphine/naloxone for opioid dependence achieved adequate postoperative pain control with buprenorphine/naloxone exclusively.  Her pain regimen included buprenorphine/naloxone 24/6 mg daily, her baseline dose, and an additional 12/3 mg every 6 hours.  

Methadone

Methadone displays analgesic properties that have been successful for chronic pain management.^7,27  Methadone’s duration of analgesia is about 6 to 8 hours, which is significantly shorter than its action to prevent withdrawal. Because of the differences in duration of effect, patients receiving once daily methadone do not achieve adequate analgesia.  For patients maintained on methadone for OUD, it is recommended to utilize short-acting opioids in addition to the baseline maintenance methadone dose for pain management.³  These patients typically have a high opioid tolerance, which may require more opioids in order to achieve pain relief as compared to the typical patient.²⁷  A retrospective chart review examined acute pain treatment with morphine in methadone maintenance patients (n=67) versus non-methadone patients (n=67).²⁸  Although median morphine dose received did not differ between groups (5.07 vs. 6.67 mg), methadone maintenance patients were found to have a longer length of stay (4 vs. 7 days) and several patients (12%) required an increase in methadone dose during hospitalization.

Naltrexone

As previously described, the opioid antagonist properties of naltrexone block further binding of opioids and subsequent analgesic effects.³  Because of this, acute pain management strategies are based primarily on whether pain is anticipated (eg, a pre-planned procedure) or unanticipated (eg, an unplanned procedure or trauma).  For anticipated acute pain, the ASAM recommends discontinuing oral and intramuscular naltrexone at least 72 hours and 30 days, respectively, prior to a planned surgical procedure. Following the discontinuation of naltrexone, opioid agents can be used successfully for pain management.  A case report of a 27 year old man who was maintained on extended release intramuscular naltrexone for OUD detailed safe and effective pain management following a mastectomy.²⁹  Naltrexone was held for an unspecified period of time prior to his procedure, and successful postoperative pain management consisted exclusively of tramadol.  Naltrexone was reinitiated 2 weeks after the surgery.

In the event of unanticipated acute pain, these pre-emptive strategies cannot be employed.  High doses of opioids may be utilized to overcome naltrexone’s inhibitory effects; however, limited evidence is available to guide safe and effective use of this strategy for pain management.¹¹  When high dose opioids are utilized in an attempt to overcome naltrexone effects, patients should be closely monitored for signs of overdose.³⁰  Because overcoming opioid antagonist effects may not be effective, pain management suggestions include regional analgesia and non-opioid agents.  ASAM also recommends NSAIDs for pain management in patients receiving naltrexone.³

Active Addiction

Recommendations for acute pain management in patients with an active addiction aim to not only provide optimal analgesia, but also prevent acute withdrawal.¹¹ Opioid agonists should be utilized to maintain baseline opioid requirements in the inpatient setting.^11,18  Converting heroin to morphine equivalents can be challenging due to the varying purity of heroin.  Based on 1 conversion recommendation that utilizes an average heroin purity of 40%, 1 bag of heroin (100 mg) equals morphine 15-30 mg.  Using the approximate opioid conversion, opioid agonists may be initiated to establish a basal opioid requirement.  While short-acting opioids are beneficial for ease of titration, their short half-life may also increase risk of withdrawal.  To help mitigate both the risk of withdrawal and baseline opioid tolerance, it has been recommended to use frequent dosing intervals (every 2 to 3 hours) and transition to long-acting opioids (with short-acting opioids as needed for breakthrough pain) as soon as possible.

Summary

Various strategies have been employed for acute pain management in patients with OUD.  All strategies involve optimizing non-opioid analgesic medications initially.  If use of opioids are required, they should be individualized based on patient characteristics and preferences.  While there is a lack of strong evidence guiding management, Table 2 outlines the various strategies discussed in the preceding sections.

Table 2. Summary of management strategies based on remission status and MAT agents.^3,7,11,21

References

1.         American Psychiatric Association. Substance-related and addictive disorders. In. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013.

2.         Substance use disorders. Substance Abuse and Mental Health Services Administration website. https://www.samhsa.gov/disorders/substance-use. Updated October 27, 2015.  Accessed August 24, 2018.

3.         Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) national practice guideline for the use of medications in the treatment of addiction involving opioid use. J Addict Med. 2015;9(5):358-367.

4.         Treatments for substance use disorders. Substance Abuse and Mental Health Services Administration website. https://www.samhsa.gov/treatment/substance-use-disorders#opioid. Updated June 13, 2018. Accessed September 13, 2018.

5.         Kleber HD, Weiss RD, Anton RF, Jr., et al. for the American Psychiatric Association Work Group on Substance Use Disorders. Practice guideline for the treatment of patients with substance use disorders. 2^nd  edition. Am J Psychiatry. 2007;164(4 Suppl):5-123.

6.         Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014;33(4):451-459.

7.         Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med. 2006;144(2):127-134.

8.         Clinical Pharmacology [database online]. Tampa, FL: 2018. https://www.clinicalpharmacology-ip.com/default.aspx.  Accessed September 13, 2018.

9.         Drugs@FDA: FDA Approved Drug Products. U.S. Food & Drug Administration website. https://www.accessdata.fda.gov/scripts/cder/daf/.  Accessed September 13, 2018.

10.       Lexi-Drugs Online [database online]. Hudson, OH: 2018. https://online.lexi.com/lco/action/home.  Accessed September 13, 2018.

11.       Donroe JH, Holt SR, Tetrault JM. Caring for patients with opioid use disorder in the hospital. CMAJ. 2016;188(17-18):1232-1239.

12.       Dever C. Treating acute pain in the opiate-dependent patient. J Trauma Nurs. 2017;24:292-299.

13.       Wachholtz A, Gonzalez G. Co-morbid pain and opioid addiction: long term effect of opioid maintenance on acute pain. Drug Alcohol Depend. 2014;145:143-149.

14.       Suzuki J, Meyer F, Wasan AD. Characteristics of medical inpatients with acute pain and suspected non-medical use of opioids. Am J Addict. 2013;22(5):515-520.

15.       Bryson EO. The perioperative management of patients maintained on medications used to manage opioid addiction. Curr Opin Anaesthesiol. 2014;27(3):359-364.

16.       Bounes V, Palmaro A, Lapeyre-Mestre M, Roussin A. Long-term consequences of acute pain for patients under methadone or buprenorphine maintenance treatment. Pain Physician. 2013;16(6):e739-747.

17.       Laroche F, Rostaing S, Aubrun F, Perrot S. Pain management in heroin and cocaine users. Joint Bone Spine. 2012;79(5):446-450.

18.       Raub JN, Vettese TE. Acute pain management in hospitalized adult patients with opioid dependence: a narrative review and guide for clinicians. J Hosp Med. 2017;12(5):375-379.

19.       Substance Abuse and Mental Health Services Administration. Managing chronic pain in adults with or in recovery from substance use disorders. In. Treatment Improvement Protocol (TIP) Series 54. HHS Publication No. (SMA) 12-4671. Rockville, MD: Substance Abuse and Mental health Services Administration; 2011.

20.       Heit HA, Gourlay DL. Buprenorphine: new tricks with an old molecule for pain management. Clin J Pain. 2008;24(2):93-97.

21.       Ward EN, Quaye AN, Wilens TE. Opioid use disorders: perioperative management of a special population. Anesth Analg. 2018;127(2):539-547.

22.       Chern SY, Isserman R, Chen L, Ashburn M, Liu R. Perioperative pain management for patients on chronic buprenorphine: a case report. J Anesth Clin Res. 2013;3(250).

23.       McCormick Z, Chu SK, Chang-Chien GC, Joseph P. Acute pain control challenges with buprenorphine/naloxone therapy in a patient with compartment syndrome secondary to McArdle's disease: a case report and review. Pain Med. 2013;14(8):1187-1191.

24.       Silva M, Rubinstein A. Continuous perioperative sublingual buprenorphine. J Pain Palliat Care Pharmacother. 2016;30(4):289-293.

25.       Leighton BL, Crock LW. Case series of successful postoperative pain management in buprenorphine maintenance therapy patients. Anesth Analg. 2017;125(5):1779-1783.

26.       Book SW, Myrick H, Malcolm R, Strain EC. Buprenorphine for postoperative pain following general surgery in a buprenorphine-maintained patient. Am J Psychiatry. 2007;164(6):979.

27.       Eyler EC. Chronic and acute pain and pain management for patients in methadone maintenance treatment. Am J Addict. 2013;22(1):75-83.

28.       Hines S, Theodorou S, Williamson A, Fong D, Curry K. Management of acute pain in methadone maintenance therapy in-patients. Drug Alcohol Rev. 2008;27(5):519-523.

29.       Israel JS, Poore SO. The clinical conundrum of perioperative pain management in patients with opioid dependence: lessons from two cases. Plast Reconstr Surg. 2013;131(4):e657-e658.

30.       Vivitrol [package insert]. Waltham, MA: Alkermes; 2015.

Prepared by:

Amanda Gerberich, PharmD

PGY2 Drug Information Resident

College of Pharmacy

University of Illinois at Chicago

October 2018

The information presented is current as of September 17, 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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Probiotics and Clostridium difficile infections: What do we know now?

Background

Previously, the Drug Information Group discussed available evidence for probiotics in patients with Clostridium difficile, which can be accessed here.¹ This review aims to discuss and provide clinicians with the latest data on the use of probiotics in adults and children for the prevention and treatment of C. difficile infection (CDI).

This review includes randomized controlled trials (RCTs), meta-analyses, and observational trials evaluating the efficacy of probiotics for the prevention and treatment of CDI since the last review (April 2016) through June 2018. In expanding what is known about probiotics and C. difficile, studies have evaluated different endpoints to show possibilities for the prevention and treatment of CDI. Some trials measured antibiotic associated diarrhea (AAD), which is caused by antibiotics that disturb the colonization resistance of gastrointestinal flora.² Other studies separate C. difficile associated diarrhea (CDAD) and CDI. The former is defined as participants with diarrhea and laboratory evidence of C. difficile, while the latter is defined as a positive stool sample with an infection.^1,2

To further investigate the effectiveness and safety of probiotics for the prevention and treatment of CDI, this review will discuss the most recent clinical guidelines and summarize key evidence on probiotic use and administration. 

Guidelines

The Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) released a 2017 update to their previous 2010 guideline.³  The organization does not support the use of probiotics for the primary prevention of CDI or as a recommended treatment strategy in recurrent CDI. For both settings, the authors note that positive data exists, but due to limitations in the data they felt that there was a lack of sufficient data to make a recommendation for use. 

The American Society of Colon and Rectal Surgeons latest clinical guideline was released in 2015. The organization provided a weak recommendation for use of probiotics in both the treatment and prevention of CDAD.⁴ The guideline provided a strong recommendation for the coordinated use of antibiotics, probiotics, and toxic binding agents (cholestyramine and colestipol) for patients with recurrent or recalcitrant CDI. Recurrent CDI is defined as 3 or more unformed stools within 24 hours plus a positive fecal sample for C. difficile.

The American College of Gastroenterology released their guideline for the diagnosis, treatment and prevention of CDI in 2013.⁵ The organization notes that available evidence does not support use of supplement probiotics to decrease recurrent CDI. There is some weak data suggesting Saccharomyces boulardii may be efficacious; however, based on the potential risks, the use of probiotics is not recommended. It was also reported that there is not enough data to show probiotics prevent CDI despite moderate evidence showing probiotics decrease the incidence of AAD. 

Key evidence on probiotics use

Table 1 is a summary of the most recent data gathered from May 2016 to June 2018. This includes three studies and four meta-analyses evaluating probiotics in adults and/or children in the inpatient or outpatient setting for the prevention of CDI, CDAD, and/or AAD. No studies were identified that evaluated use of probiotics in the treatment of CDI.  

Table 1. Recent data on the use of probiotics in adults and/or children with C. difficile to prevent or treat CDI and/or CDAD, and AAD.

In summary, meta-analyses support the use of probiotics in the prevention of CDI and/or CDAD.^2,8,9,11 While the 2 small studies from Ehrhardt and Alberda found no evidence to support probiotics use in patients to prevent AAD.^6,7 However, both studies were underpowered, as the Ehrhardt RCT was terminated early due to slow recruitment and a low incidence of AAD and the Alberda RCT was a pilot study. The study by Carstensen did find a reduction in the monthly mean incidence of CDI after a protocol was introduced to encourage probiotic use; however, its design makes it difficult to establish a causal relationship between the intervention and CDI events.¹⁰ Serious adverse events were variable and statistically insignificant across the studies included in table 1.

In the meta-analyses, some of the subgroup analyses provided insight into the best use of probiotics, either related to the formulation used or population targeted. A meta-analysis by Johnston showed probiotics to be useful in the prevention of CDI, but in a subgroup analysis it was shown that only multistrain probiotics were effective as single strain probiotics were not better than the control.⁸ Shen found evidence that in hospitalized high-risk adult patients, intervention within 2 days of the first dose of antibiotic treatment was necessary to observe a reduction in the incidence of CDI.⁹ The meta-analysis from Lau found that probiotic supplementation is a valuable adjunct for patients receiving antibiotic therapy to prevent CDAD, but this effect only extended to hospitalized patients, as probiotic use in the outpatient population did not have a significant impact on CDAD rates.¹¹ Additionally, in analyzing specific strains, Lau found that using either Lactobacillus, Saccharomyces, or a mixture of probiotics were beneficial in reducing the risk of CDAD. Goldenberg stratified their analysis by baseline risk and found that probiotics were only beneficial in reducing the risk of CDAD in patients with a baseline risk >5%. ²

Strain specificity

According to the IDSA/SHEA 2017 guideline, there are no specific strain(s) of probiotics that show reproducible efficacy to prevent CDI and/or CDAD.³ Although the guideline does not support any one strain, dose or duration, there is evidence that promises otherwise for AAD, and possibly for CDI.

An analysis of 6 types of Lactobacillus strains found that 4 significantly reduced the incidence of AAD in adults.¹² L. casei-DN-114001 (relative risk [RR], 0.32; 95% confidence interval [CI], 0.16 to 0.63), L. reuteri ATCC 55730 (RR, 0.35; 95% CI, 0.20 to 0.61), a mixture strain of L. acidophilus CL1285, L. casei LBC80R, and L. rhamnosus CLR2, Bio-K+^®, (RR, 0.56; 95% CI, 0.40 to 0.79), and a mixture strain of L. acidophilus La5 and B. lactis Bb12 (RR, 0.67; 95% CI, 0.47 to 0.94) all significantly reduced the incidence of AAD. In another analysis, indirect comparisons were conducted to provide relative rankings of 10 probiotic preparations for the prevention of AAD and CDI.¹³ For effectiveness in preventing CDI, L. casei and L. acidophilus ranked as the top 2 probiotics, with both showing superiority to placebo on network meta-analysis (odds ratio [OR], 0.04; 95% CI, 0.00 to 0.77 and OR, 0.20; 95% CI, 0.08 to 0.48). Additionally, the analysis also evaluated tolerability and found L. rhamnosus GG to be one of the most well-tolerated strains.

Overall, identifying the best strain is challenging based on variations in individual studies and while meta-analyses attempt to resolve these issues, some of the estimates are based on pooled data from only 2 RCTs. For CDI specifically, Johnston et al found that using multispecies probiotics (OR, 0.33; 95% CI, 0.20 to 0.56) significantly reduced CDI rates compared to single strain probiotics (OR, 0.41; 95% CI, 0.17 to 1.00).⁸ Therefore, further comparative evaluations of specific strains, doses, and duration are needed to recommend an optimum regimen. It is also important for clinicians to consider the potential risks of probiotics therapy in high risk patients. These risk factors were discussed in the previous FAQ document.¹ However, one of the most concerning is the potential to cause infections, including bacteremia, especially in immunosuppressed patients.¹⁴  

Conclusion

Overall, the most recent meta-analyses do support the use of probiotics for the prevention of CDI. ^2,8,9,11 However, several limitations should be noted about the trials incorporated into the meta-analyses. Several studies did not evaluate the impact on CDI or CDAD rates and instead focused on AAD, which is not necessarily relevant to prevention of CDI. Additionally, there are varying definitions of the outcomes used across the trials and a variety of probiotic strains, doses, and durations used. Based on those limitations, the most recent IDSA/SHEA guideline does not promote the use of probiotics for the primary prevention of CDI or as a recommended treatment strategy in recurrent CDI.³

As of now, clinicians are left to decide who would potentially benefit from probiotic administration with an antibiotic prescription and the most effective regimen. It does appear that probiotics are potentially most effective in patients with a higher baseline risk for CDI. Some factors associated with a higher risk of CDI development with antibiotic administration include age over 65 years, use of high risk antibiotics (cephalosporins, penicillins, and fluoroquinolones), and prolonged exposure to the healthcare environment (eg, intensive care unit stay).¹⁵ As far as preferred probiotic regimens, use of multistrain formulations and Lactobacillus strains appear most promising in the prevention of CDI.^8,11-13 

References

1. What is the most recent evidence for using probiotics in patients with Clostridium difficile? UIC Drug Information Group website. https://pharmacy.uic.edu/departments/pharmacy-practice/centers-and-sections/drug-information-group/2014/2016-faq-s/apr-2016-faqs. Published April 2016.
2. Goldenberg JZ, Yap C, Lytvyn L, et. al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017;12:CD006095.
3. McDonald CL, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7): 987-994.
4. Steele SR, McCormick J, Melton GB, et al. Practice parameters for the management of Clostridium difficile infection. Dis Colon Rectum. 2015;58(1):10-24.
5. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile Infections. Am J Gastroenterol. 2013;108(4):478-498.
6. Ehrhardt S, Guo N, Hinz R, et al. Saccharomyces boulardii to prevent antibiotic-associated diarrhea: a randomized, double-masked, placebo-controlled trial. Open Forum Infect Dis. 2016;3(1):ofw011. doi: 10.1093/ofid/ofw011.
7. Alberda C, Marcushamer S, Hewer T, Journault N, Kutsogiannis D. Feasibility of a Lactobacillus casei drink in the intensive care unit for prevention of antibiotic associated diarrhea and Clostridium difficile. Nutrients. 2018;10(5). doi: 10.3390/nu10050539.
8. Johnston BC, Lytvyn L, Lo CK, et al. Microbial preparations (probiotics) for the prevention of Clostridium difficile infection in adults and children: an individual patient data meta-analysis of 6,851 participants. Infect Control Hosp Epidemiol. 2018;39(7):771-781.
9. Shen NT, Maw A, Tmanova LL, et al. Timely use of probiotics in hospitalized adults prevents Clostridium difficile infection: A systematic review with meta-regression analysis. Gastroenterol. 2017;152(8):1889-1900.
10. Carstensen JW, Chehri M, Schonning, et al. Use of prophylactic Saccharomyces boulardii to prevent Clostridium difficile infection in hospitalized patients: a controlled prospective intervention study. Eur J Clin Microbiol Infect Dis. 2018;37(8):1431-1439.
11. Lau CS, Chamberlain RS. Probiotics are effective at preventing Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Int J Gen Med. 2016;9:27-37.
12. Mcfarland LV, Evans CT, Goldstein EJC. Strain-specificity and disease-specificity of probiotic efficacy: a systematic review and meta-analysis. Front Med. 2018;5:124.
13. Cai J, Zhao C, Du Y, Zhang Y, Zhao M, Zhao Q. Comparative efficacy and tolerability of probiotics for antibiotic associated diarrhea: Systematic review with network meta-analysis. United European Gastroenterol J. 2018;(6)2:169-180.
14. Gouriet F, Million M, Henri M, Fournier PE, Raoult D. Lactobacillus rhamnosus bacteremia: an emerging clinical entity. Eur J Clin Microbiol Infect Dis. 2012;31(9):2469-2480.
15. Eze P, Balsells E, Kyaw MH, Nair H. Risk factors for Clostridium difficile infections- an overview of the evidence base and challenges in data synthesis. J Glob Health 2017; 7:010417. doi: 10.7189/jogh.07.010417.

Prepared by:

Danerra Grahn, PharmD Candidate 2020

College of Pharmacy

University of Illinois at Chicago

Reviewed by:

Samantha Spencer, PharmD, BCPS

Clinical Assistant Professor

College of Pharmacy

University of Illinois at Chicago

October 2018

The information presented is current as of June 15, 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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