June 2018 FAQs

What is the current evidence on using aromatherapy for treating postoperative nausea and/or vomiting?

Background

Postoperative nausea and vomiting (PONV) affect a large number of patients with 30% of patients experiencing vomiting and 50% of patients having nausea.1 Prolonged stay in postanesthesia care unit and hospital admission are some of the adverse outcomes associated with PONV. Patient-specific factors, type and duration of surgery, and anesthesia-related factors cause the release of 5-hydroxytryptamine (5-HT) from the central nervous system and gastrointestinal tract.2 Mainly, 5-HT subtype 3 receptor (5-HT3) is responsible for nausea and vomiting.

An essential oil is an aromatic oil from a plant that is extracted via distillation, hydrodiffusion, or pressure; while aromatherapy is a practice of using essential oils for therapeutic purposes.3 Although essential oils are available pure, they can also be diluted in a carrier oil such as canola, sunflower, olive, jojoba, or almond oil. For PONV, the proposed mechanism of action involves binding of aroma to receptors in the nasal epithelium leading to transmission of neurochemical reactions through olfactory bulb, limbic system, and thalamus that results in endorphin release.4 The most common routes for administration of essential oils are topical and inhalation.3 

Current guidelines

The Society for Ambulatory Anesthesia published the most recent guideline for the management of PONV in 2014.1 The guideline identifies patients at highest risk for developing PONV:

  • age < 50 years;
  • cholecystectomy, gynecologic, or laparoscopic procedures;
  • female gender;
  • non-smoker status;
  • history of motion sickness;
  • use of volatile anesthetics and nitrous oxide;
  • duration of anesthesia;
  • use of opioids postoperatively.

The guideline provides recommendations on both prophylaxis and treatment of PONV. The preferred agent for the treatment of PONV is low-dose 5-HT3 receptor antagonist in patients who have not received prophylaxis. If a patient took a prophylactic agent and then developed PONV, an agent from a different pharmacological class should be administered. Other options for treatment of PONV besides 5-HT3 antagonists consist of intravenous dexamethasone, droperidol, promethazine, or propofol. The guideline mentions that isopropyl alcohol inhalation is not effective for the prophylaxis of PONV, but aromatherapy with isopropyl alcohol may be effective in treatment with effects such as quicker reduction of nausea severity when compared to promethazine or ondansetron. However, additional studies with appropriate design are necessary to assess the true effect of this intervention.

Evidence

A literature search utilizing terms such as aromatherapy, essential oils, nausea, and vomiting identified a recent Cochrane review and a study published after the release of the Cochrane review. The Cochrane review on the use of aromatherapy for the treatment of PONV performed a comprehensive literature search through March 2, 2017.5 Therefore, individual studies published before that date are not discussed.

The Cochrane review published in 2018 explored the efficacy of aromatherapy in the treatment of PONV.5 The review included 16 controlled trials with 1,036 patients in total. Most of the studies focused on adult population except for 2 studies that also enrolled children. Patients received aromatherapy via direct inhalation of vapors at the first complaint of nausea right after surgical procedure. The most common essential oils or agents used as part of aromatherapy were isopropyl alcohol, peppermint oil, ginger, or mixtures including some of these agents and others such as spearmint, cardamom, and lavender. Aromatherapy did not reduce the severity of nausea and duration of nausea compared to placebo. However, with aromatherapy, fewer patients required rescue anti-nausea medications compared to placebo (risk ratio (RR), 0.60; 95% confidence interval (CI), 0.37 to 0.97). Most promising results were with aromatherapy involving isopropyl alcohol. Patients receiving isopropyl alcohol experienced a faster reduction in nausea compared to standard anti-emetics such as ondansetron and promethazine (standard mean difference, -1.10 min; 95% CI, -1.43 to -0.78). Fewer patients in the isopropyl alcohol group used rescue anti-emetics compared to the standard treatment for PONV (RR, 0.67; 95% CI, 0.46 to 0.98); however, comparison to the saline treatment did not reveal any statistical significance (RR, 0.39; 95% CI, 0.12 to 1.24). Patients in both groups, aromatherapy and placebo, reported high levels of satisfaction with treatment, which authors attributed to increased attention for managing PONV. The included studies did not report any adverse events to aromatherapy. The authors of the Cochrane review rate the included studies as moderate to very low quality. Study design issues included lack of blinding to group allocation; differences in comparisons, measurement scales, and time periods; and missing data for assessing efficacy over a longer time period. The authors of the Cochrane review concluded that isopropyl alcohol vapor inhalation is an option if patients refuse anti-emetics, if anti-emetics are contraindicated, or if they are unavailable. Peppermint aromatherapy does not reduce nausea severity, and aromatherapy with ginger and other mixtures has incomplete evidence.

Since the publication of the Cochrane review, another prospective randomized trial involving aromatherapy for PONV was published. A study by Stallings-Welden and colleagues explored the effects of aromatherapy (a blend of spearmint, peppermint, ginger, and lavender essential oils) versus pharmacological treatment of PONV in 221 patients.6 The effectiveness of PONV relief was not statistically different between the 2 groups.

Safety

Although essential oils are relatively safe, practitioners should be aware of potential safety issues.4 The Food and Drug Administration (FDA) does not review efficacy and safety of essential oils before they are marketed; however, the FDA gets involved if a safety issue arises.3 The most common adverse effects are skin irritation, photosensitivity, and airway irritation. Topical application of a pure essential oil is the main reason for skin irritation or contact dermatitis.3,7 Mixing carrier oil with essential oils can decrease the risk of contact irritation, and only trained personnel should apply undiluted essential oils directly to the skin.3 Severe adverse effects are rare but can include seizures and pneumonitis, especially in the pediatric population. The evidence on long-term use is lacking, and therefore, patients should receive essential oils in moderation. Patients with lung problems, children, and pregnant women should avoid the use of essential oils.3,4

Preparation and administration

The preparation and administration of essential oils used in aromatherapy for PONV depend on the product. For isopropyl alcohol aromatherapy, most study protocols used commercially available alcohol pads or cotton balls soaked in 70% isopropyl alcohol.8-13 Typically, a patient with PONV placed a pad or cotton ball 0.5 to 1 inches away from nares and took 3 deep inhalations. The patient could repeat the process 3 times every 5 to 15 minutes. Peppermint aromatherapy involved the application of pharmacy grade peppermint spirits to a cotton ball.14-17 Patients inhaled directly from the cotton ball or from a plastic container containing the cotton ball if the need existed to limit exposure to the surrounding air. Similarly, patients performed 3 deep breaths and could repeat them up to 3 times.

Conclusion

The incidence of PONV remains high, and an interest in the use of aromatherapy for treatment of PONV exists. The most recent literature shows promising results with isopropyl alcohol vapor inhalation compared to standard antiemetic drugs. The inhalation of isopropyl alcohol may reduce nausea faster and contribute to the lower use of rescue anti-emetics. The comparison of isopropyl alcohol aromatherapy to saline did not show any statistically significant results for managing PONV. Thus, aromatherapy with isopropyl alcohol is a potential option for patients refusing or not tolerating anti-emetics or if anti-emetics are unavailable. However, the quality of evidence is moderate to very low, and robust studies are necessary to assess the true effects of isopropyl alcohol in PONV.

References

1.         Gan TJ, Diemunsch P, Habib AS, et al. Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2014;118(1):85-113.

2.         Shaikh SI, Nagarekha D, Hegade G, Marutheesh M. Postoperative nausea and vomiting: a simple yet complex problem. Anesth Essays Res. 2016;10(3):388-396.

3.         Manion CR, Widder RM. Essentials of essential oils. Am J Health Syst Pharm. 2017;74(9):e153-e162.

4.         O'Malley PA. Aromatherapy for postoperative nausea in acute care-evidence and future opportunities. Clin Nurse Spec. 2016;30(6):318-320.

5.         Hines S, Steels E, Chang A, Gibbons K. Aromatherapy for treatment of postoperative nausea and vomiting. Cochrane Database Syst Rev. 2018;3:CD007598.

6.         Stallings-Welden LM, Doerner M, Ketchem EL, Benkert L, Alka S, Stallings JD. A comparison of aromatherapy to standard care for relief of PONV and PDNV in ambulatory surgical patients. J Perianesth Nurs. 2018;33(2):116-128.

7.         de Groot AC, Schmidt E. Essential oils, part IV: contact allergy. Dermatitis. 2016;27(4):170-175.

8.         Cotton JW, Rowell LR, Hood RR, Pellegrini JE. A comparative analysis of isopropyl alcohol and ondansetron in the treatment of postoperative nausea and vomiting from the hospital setting to the home. AANA J. 2007;75(1):21-26.

9.         Pellegrini J, DeLoge J, Bennett J, Kelly J. Comparison of inhalation of isopropyl alcohol vs promethazine in the treatment of postoperative nausea and vomiting (PONV) in patients identified as at high risk for developing PONV. AANA J. 2009;77(4):293-299.

10.       Hunt R, Dienemann J, Norton HJ, et al. Aromatherapy as treatment for postoperative nausea: a randomized trial. Anesth Analg. 2013;117(3):597-604.

11.       Merritt BA, Okyere CP, Jasinski DM. Isopropyl alcohol inhalation: alternative treatment of postoperative nausea and vomiting. Nurs Res. 2002;51(2):125-128.

12.       Wang SM, Hofstadter MB, Kain ZN. An alternative method to alleviate postoperative nausea and vomiting in children. J Clin Anesth. 1999;11(3):231-234.

13.       Winston AW, Rinehart RS, Riley GP, Vacchiano CA, Pellegrini JE. Comparison of inhaled isopropyl alcohol and intravenous ondansetron for treatment of postoperative nausea. AANA J. 2003;71(2):127-132.

14.       Anderson LA, Gross JB. Aromatherapy with peppermint, isopropyl alcohol, or placebo is equally effective in relieving postoperative nausea. J Perianesth Nurs. 2004;19(1):29-35.

15.       Ferruggiari L, Ragione B, Rich ER, Lock K. The effect of aromatherapy on postoperative nausea in women undergoing surgical procedures. J Perianesth Nurs. 2012;27(4):246-251.

16.       Lane B, Cannella K, Bowen C, et al. Examination of the effectiveness of peppermint aromatherapy on nausea in women post C-section. J Holist Nurs. 2012;30(2):90-104; quiz 105-106.

17.       Sites DS, Johnson NT, Miller JA, et al. Controlled breathing with or without peppermint aromatherapy for postoperative nausea and/or vomiting symptom relief: a randomized controlled trial. J Perianesth Nurs. 2014;29(1):12-19.

The information presented is current as of May 10, 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 data are available to support etelcalcetide in hemodialysis patients with secondary hyperparathyroidism?

Chronic Kidney Disease and Secondary Hyperparathyroidism

Chronic kidney disease (CKD) affects a significant portion of the US population, with an estimated prevalence of 14.8% in years 2011 to 2014.1 In fact, approximately 700,000 patients in the US had end stage renal disease (ESRD) in 2015, of whom 63% were treated with hemodialysis (HD) and 7% with peritoneal dialysis (PD). One potential complication of CKD is secondary hyperparathyroidism (SHPT).2

Secondary hyperparathyroidism is a condition characterized by an abnormal increase in the secretion of parathyroid hormone (PTH), which may result in hyperplasia of the parathyroid gland.3 In patients with CKD, renal function is impaired, which causes phosphate retention along with an inability to activate vitamin D to calcitriol. The parathyroid gland is continuously stimulated by these high phosphate concentrations, along with low calcium and low calcitriol concentrations; this results in elevated PTH.2,3 In SHPT, several complications may develop, including renal osteodystrophy and vascular calcification contributing to cardiovascular disease.2-4

Guidelines

In adult patients with CKD stages 3a to 5 who are currently not on dialysis, the 2017 Kidney Disease: Improving Global Outcomes (KDIGO) guideline update for chronic kidney disease-mineral and bone disorder (CKD-MBD) suggests that patients who have progressively rising or elevated PTH levels be evaluated for modifiable factors such as hyperphosphatemia, hypocalcemia and vitamin D deficiency.5 The KDIGO guideline also suggests reserving the use of calcitriol and vitamin D analogs for patients with CKD stages 4 to 5 with severe and progressive hyperparathyroidism.

For patients with CKD stage 5, the KDIGO guideline suggests maintaining intact parathyroid hormone (iPTH) at 2 to 9 times the upper normal limit for the assay.5 Rapid changes in this range should prompt an initiation or change in therapy. The guideline suggests using calcimimetics (ie, cinacalcet), calcitriol, vitamin D analogs, or calcimimetics plus calcitriol or vitamin D analogs in patients who need PTH lowering therapy. Parathyroidectomy is suggested in patients with CKD stages 3a to 5 who have failed to respond to medical or pharmacologic therapy.

The Kidney Disease Outcomes Quality Initiative (KDOQI) CKD-MBD workgroup provided a commentary in response to the KDIGO 2017 updated guideline.6 The commentary supports most of the changes in the updated guideline; however, the workgroup expressed some concerns and additional commentary. For the treatment of abnormal PTH in CKD stage 5 dialysis patients, the workgroup recommends choosing medications based on patient specific factors, specifically serum calcium and phosphate levels.

The KDIGO 2017 guideline states that randomized controlled trials (RCTs) for etelcalcetide were published after the systematic review for the guideline and did not influence the guideline recommendations.5 One criticism of the RCTs was that they lacked patient-centered endpoints. Both the KDIGO guideline and KDOQI commentary recommend the need for future RCTs for etelcalcetide which evaluate its effect on patient-centric outcomes, such as left ventricular mass, cardiovascular events, mortality, and hospitalizations.5,6

Etelcalcetide

Etelcalcetide (Parsabiv®) is a calcimimetic that was approved by the Food and Drug Administration (FDA) in 2017 for the treatment of SHPT in adult patients with CKD on HD.7 Etelcalcetide decreases PTH secretion by binding the calcium-sensing receptor on parathyroid chief cells, resulting in enhanced activation of the receptor by extracellular calcium. Etelcalcetide is administered intravenously three times per week at the end of HD treatment. The dose is individualized and titrated based on PTH and corrected calcium response.

Literature Summary

Trials evaluating etelcalcetide for SHPT in dialysis patients are reported in the Table. Etelcalcetide was compared to placebo in 3 RCTs and was efficacious in short-term reduction of iPTH, defined as the proportion of patients with iPTH between 60 to 240 pg/mL at 12 weeks or a > 30% reduction from baseline over 26 weeks.8,9 Compared to placebo, patients who received etelcalcetide generally experienced a greater number of gastrointestinal adverse events (AEs) and symptomatic hypocalcemia. In one open-label study over 52 weeks, etelcalcetide treatment was effective for long term use, defined as the proportion of patients with iPTH between 60 to 240 pg/mL.10 The proportion of patients achieving control grew from 6.3% at baseline to 87.5% on day 365, with similar AEs observed from the short-term RCTs. Only one RCT has compared etelcalcetide to an active comparator, cinacalcet.11 Etelcalcetide was non-inferior and superior to cinacalcet for reducing iPTH by > 30% over 26 weeks from baseline, with a similar safety profile between the 2 therapies.

The studies of etelcalcetide have limitations. For example, 2 of the RCTs only included Japanese patients, which may limit generalizability to other patient populations.9,10 Also, only one of the studies compared etelcalcetide to an active comparator, and only one study was longer than 26 weeks.10,11 Additionally, as noted in the KDIGO updated guideline, the trials did not evaluate patient-centric outcomes.5,8-11

Table. Summary of Evidence for Etelcalcetide for SHPT in Dialysis.

Study Design

Subjects

Interventions

Endpoints

Conclusion

Shigematsu 201810

OL, MC

N=191 Japanese patients ≥ 20 years old receiving HD treatment 3 times per week for at least 90 days with SHPT and iPTH > 240 pg/mL, corrected Ca ≥ 8.4 mg/dL and dialysate Ca ≥ 2.25 mEq/L

Etelcalcetide 5 mg IV three times weekly (adjusted to 2.5 to 15 mg every 4 weeks) (n=191)

Treatment duration: 52 weeks

Allowed concurrent medications: phosphate binders, Ca supplements, calcitriol and active vitamin D analogs

Dose adjustments for concurrent medications were allowed during the study

Efficacy:

Proportion of patients with iPTH between 60 to 240 pg/mL was 6.3% (95% CI, 3.3% to 10.8%) on day 1, 60.5% (95% CI, 52.8% to 67.7%) on day 85, 73.8% (95% CI, 66.6 to 80.2%) on day 169 and 87.5% (95% CI, 81.4 to 92.2%) on day 365*

Mean iPTH decreased from 472.5 ± 248.8 pg/mL on day 1 to 162.8 ± 157.4 pg/mL on day 85 and 157 ± 130.5 pg/mL on day 365*

Safety:

Treatment-emergent AEs were reported in 96.8% of patients with 27.9% considered treatment-related.

Treatment-related AEs: nausea (0.5%), vomiting (1.1%), symptomatic hypocalcemia (1.1%)

1.1% of patients died

Etelcalcetide was effective and safe for long term control of iPTH in CKD patients on HD.

Block 201711

DB, MC, AC, RCT

N=683 patients ≥ 18 years old receiving HD treatment 3 times per week for ≥ 3 months with SHPT and iPTH > 500 pg/mL, Ca ≥ 8.3 mg/dL and dialysate Ca ≥ 2.25 mEq/L

Etelcalcetide 5 mg IV three times weekly (adjusted to 2.5 to 15 mg) (n=340)

Cinacalcet 30 mg PO daily (adjusted to 30 to 180 mg) (n=343)

Dose adjustments at weeks 5, 9, 13, and 17

Treatment duration: 26 weeks

Allowed concurrent medications: phosphate binders, Ca supplements, calcitriol and active vitamin D analogs

Primary:

Proportion of patients with > 30% reduction from baseline in mean iPTH during weeks 20 to 27 was 68.2% with etelcalcetide and 57.7% with cinacalcet (difference, -10.5%; 95% CI, -17.5% to -3.5%; p<0.001 for noninferiority;

p<0.004 for superiority [secondary endpoint])

Noninferiority margin: 12.0%

Secondary:

Proportion of patients with > 50% reduction from baseline in mean iPTH during weeks 20 to 27 was 52.4% with etelcalcetide and 40.2% with cinacalcet (difference, 12.2%; 95% CI, 4.7% to 19.5%; p=0.001)

There was no difference between groups in the adjusted mean weekly days of vomiting or nausea in the first 8 weeks.

Safety:

Incidence of select treatment-emergent AEs for etelcalcetide and cinacalcet, respectively:

  • Hypocalcemia: 68.9% vs 59.8%
  • Nausea: 18.3% vs 22.6%
  • Vomiting: 13.3% vs 13.8%
  • Death: 2.7% vs 1.8%

Etelcalcetide was noninferior and superior to cinacalcet for PTH lowering over 26 weeks. Overall safety and tolerability were similar between the 2 groups.

Block 20178

2 DB, MC, PC, parallel RCTs

N=508 patients (Trial A) and N=515 patients (Trial B) ≥18 years old receiving HD treatment 3 times per week for at least 90 days with SHPT and iPTH > 400 pg/mL, corrected Ca ≥ 8.3 mg/dL and dialysate Ca ≥ 2.25 mEq/L

Etelcalcetide 5 mg IV three times weekly (adjusted to 5 to 15 mg)

Trial A: (n=254)

Trial B: (n=255)

Placebo
Trial A: (n=254)

Trial B: (n=260)

Dose adjustments at weeks 5, 9, 13, and 17

Treatment duration: 26 weeks

Allowed concurrent medications: phosphate binders, Ca supplements, calcitriol and active vitamin D analogs

Primary:

Proportion of patients with > 30% reduction from baseline in mean PTH during weeks 20 to 27:

Trial A: 74.0% with etelcalcetide vs 8.3% with placebo

(difference, 65.7%; 95% CI, 59.4% to 72.1%; p<0.001)

Trial B: 75.3% with etelcalcetide vs 9.6% with placebo

(difference, 65.7%; 95% CI, 59.3% to 72.1%; p<0.001)

Secondary:

Proportion of patients achieving iPTH ≤ 300 pg/mL:

Trial A: 49.6% with etelcalcetide vs 5.1% with placebo (difference, 44.5%; 95% CI, 37.8% to 51.2%; p<0.001)

Trial B: 53.3% with etelcalcetide vs 4.6% with placebo (difference, 48.7%; 95% CI, 42.1% to 55.4%; p<0.001)

Safety:

Select treatment-emergent AEs for etelcalcetide in trials A and B vs placebo in trials A and B:

  • Hypocalcemia: 61.0% and 66.7% vs 8.3% and 12.0%
  • Muscle spasms: 12.0 and 11.1% vs 7.1% and 6.2%
  • Diarrhea: 7.2% and 14.3% vs 7.1% and 10.0%
  • Nausea: 12.4% and 9.1% vs 5.1% and 7.3%
  • Vomiting: 10.4% and 7.5% vs 7.1% and 3.1%
  • Death: 2.8% and 2.8% vs 1.6% and 3.1%

Etelcalcetide was efficacious in lowering iPTH in CKD patients on HD. However, it had more gastrointestinal and hypocalcemia-related AEs compared to placebo.

Fukagawa 20179

DB, MC, PC, RCT

N=155 Japanese patients ≥ 20 years old receiving HD treatment 3 times per week for at least 90 days with SHPT and iPTH ≥ 300 pg/mL, corrected Ca ≥ 8.4 mg/dL and dialysate Ca ≥ 2.25 mEq/L

Etelcalcetide 5 mg IV three times weekly (adjusted to 2.5 to 15 mg every 4 weeks) (n=78)

Placebo (n=77)

Treatment duration: 12 weeks

Allowed concurrent medications: phosphate binders, calcium supplements and active vitamin D analogs

Dose adjustments for concurrent medications were not allowed during study.

Primary:

Proportion of patients with iPTH between 60 to 240 pg/mL on day 85: 59% with etelcalcetide vs 1.3% with placebo (difference, 60.0%; 95% CI, 49.7% to 70.4%; p<0.0001)

Secondary: Proportion of patients with ≥ 30% reduction in iPTH from baseline on day 85: 76.9% with etelcalcetide vs 5.2% with placebo (p<0.0001)

Safety:

Treatment-related AEs occurred in 19.2% of patients with etelcalcetide and 3.9% with placebo. AEs observed in etelcalcetide group, but not placebo: asymptomatic reduction in blood Ca (6.4%),

vomiting (3.8%), nausea (1.3%), symptomatic hypocalcemia (1.3%)

Etelcalcetide was efficacious and safe for lowering iPTH in CKD patients on HD.

*Difference between time points was reported to be statistically significant, but p-value was not specified.

Abbreviations: AC=active control; AE=adverse event; Ca=calcium; CI=confidence interval; CKD=chronic kidney disease; DB=double blind; HD=hemodialysis; iPTH=intact parathyroid hormone; IV=intravenous; MC=multi-center; OL=open label; PC=placebo-controlled; PO=orally; RCT=randomized controlled trial; SHPT=secondary hyperparathyroidism.

Conclusion

Prior to the FDA approval of etelcalcetide, cinacalcet was the only calcimimetic available for the treatment of SHPT in adult patients with CKD on HD.11 Only 1 RCT evaluated the 2 therapies head-to-head and found that etelcalcetide was noninferior for the primary outcome of reducing iPTH by > 30% over 26 weeks from baseline; etelcalcetide had a similar safety profile to cinacalcet, with the exception of a numerically higher incidence of hypocalcemia. Etelcalcetide was also superior to cinacalcet for secondary outcomes related to PTH-lowering in this study. Currently, the KDIGO guideline recommends calcimimetics, calcitriol, vitamin D analogs, or calcimimetics plus calcitriol or vitamin D for lowering iPTH; however, the guideline does not specify a first-line treatment between the options.5 Etelcalcetide is not included in the recommendations. Additional trials evaluating the effect of etelcalcetide on patient-centric outcomes such as mortality and cardiovascular events are warranted. Results from an ongoing study focused on cardiac hypertrophy may help guide future treatment discussions.5,12

References

  1. Saran R, Robinson B, Abbott KC, et al. US Renal Data System 2017 Annual Data Report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2018;71(3)(suppl 1):Svii,S1-S672.
  2. Potts JT, Jr., Jüppner H. Disorders of the parathyroid gland and calcium homeostasis. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1130&sectionid=79753597. Accessed May 29, 2018.
  3. Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options. Clin J Am Soc Nephrol. 2011;6(4):913-921.
  4. Nikodimopoulou M, Liakos S. Secondary hyperparathyroidism and target organs in chronic kidney disease. Hippokratia. 2011;15(Suppl 1):33-38.
  5. Kidney Disease Improving Global Outcomes CKD-MBD Workgroup. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017; 7:1-59
  6. Isakova T, Nickolas TL, Denburg M, et al. KDOQI US Commentary on the 2017 KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis. 2017;70(6):737-751.
  7. Parsabiv [package insert]. Thousand Oaks, CA: Amgen; 2017.
  8. Block GA, Bushinsky DA, Cunningham J, et al. Effect of etelcalcetide vs placebo on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: two randomized clinical trials. JAMA. 2017;317(2):146-155.
  9. Fukagawa M, Yokoyama K, Shigematsu T, et al. A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients. Nephrol Dial Transplant. 2017;32(10):1723-1730.
  10. Shigematsu T, Fukagawa M, Yokoyama K, et al. Long-term effects of etelcalcetide as intravenous calcimimetic therapy in hemodialysis patients with secondary hyperparathyroidism. Clin Exp Nephrol. 2018;22(2):426-436.
  11. Block GA, Bushinsky DA, Cheng S, et al. Effect of etelcalcetide vs cinacalcet on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: a randomized clinical trial. JAMA. 2017;317(2):156-164.
  12. Effect of Etelcalcetide on Cardiac Hypertrophy in Hemodialysis Patients (EtECAR-HD). U.S. National Library of Medicine website. https://clinicaltrials.gov/ct2/show/NCT03182699. Updated February 2, 2018. Accessed May 24, 2018.

Prepared by:

Jae Hyun Lee, PharmD Candidate 2019

College of Pharmacy

University of Illinois at Chicago

Reviewed and edited by:

Patricia Hartke, PharmD

June 2018

The information presented is current as March 14, 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 guideline recommendations are available regarding perioperative multimodal analgesia (MMA)?

Introduction

More than 80% of patients who undergo surgery experience acute postoperative pain.1 Of these, approximately 75% experience pain that is moderate, severe, or extreme. The lack of pain control negatively affects outcomes such as quality of life, function, post-surgical complications, and the risk of developing persistent postsurgical pain.

Postoperative pain occurs through multiple physiological pathways.2 For example, tissue trauma from surgical incisions releases inflammatory mediators and causes hyperalgesia, whereas neurologic pain may be caused by direct nerve injury. Therefore, analgesia regimens incorporating drug therapy that targets more than one pain pathway has been proposed to better control perioperative pain.

Opioids have long been used as perioperative analgesics because of their effects at mu opioid receptors in the brain and spinal cord, which modulate the transmission of pain.3 However, opioids may cause serious acute adverse events, including nausea, vomiting, pruritis, respiratory depression, and constipation.4 Additionally, long-term risks of chronic opioid use include tolerance, dependence, addiction, and withdrawal; these concerns have been brought to wide public attention by the 4-fold increase in opioid use since the 1990s.3,5

Given the multiple mechanisms of perioperative pain and concerns related to opioids, there has been a recent shift toward incorporation of non-opioid analgesics in post-operative pain management regimens that provide multimodal analgesia (MMA), defined as the use of 2 or more drugs with different analgesic mechanisms in the peripheral and central nervous system.2,6 Presumed benefits of MMA include reducing the use and adverse events of opioids, as well as improved control of pain.3 Recently, several guidelines from pain and surgical societies have produced guidelines incorporating recommendations for the use of MMA.1,6-8 Given the variety of surgical procedures, mechanisms of drug action, and potential analgesic combinations, questions may arise regarding best practices. Therefore, this review discusses guideline recommendations on the use of MMA to improve postsurgical pain.

Components of MMA regimens

Common non-opioid analgesics used in MMA regimens include various classes of drugs traditionally used for musculoskeletal and neuropathic pain, including acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), gabapentinoids, ketamine, and tricyclic antidepressants.4,5,9 Pain mechanisms addressed by these drug classes include inhibition of cyclooxygenase (COX) enzymes by acetaminophen and NSAIDs, which provides decreased inflammation and peripheral nociception. In contrast, central actions of gabapentin, pregabalin, and ketamine inhibit NMDA receptors, which reduces the hyperexcitability of nociceptive neurons in the spinal cord.10

In addition to systemic analgesia, other pharmacologic modalities employed in MMA include local, peripheral regional, and neuraxial administration.1,6 Local infiltration of anesthetics such as lidocaine or bupivacaine temporarily reduces conduction of neural impulses, and their injection near individual nerves or nerve plexuses in peripheral regional and neuraxial administration produces larger regions of analgesia in areas distal to the site of injection.11,12 Lastly, nonpharmacologic measures may be utilized as part of MMA regimens, including cognitive-behavioral modalities (eg, guided imagery and relaxation techniques), which may modulate the emotional and psychologic components of pain experiences, and transcutaneous electrical nerve stimulation, which is believed to reduce central excitability, and thereby pain, via effects on descending nerve pathways.1,13

Guideline recommendations for MMA

Recommendations on use of perioperative MMA are provided in a 2012 guideline from the American Society of Anesthesiologists (ASA) and a 2016 joint guideline by the American Pain Society (APS), American Society of Regional Anesthesia and Pain Medicine (ASRAPM), and the American Society of Anesthesiologists (ASA).1,6 Both guidelines recommend the use of MMA whenever possible, and are consistent in recommending the use of acetaminophen, NSAIDs, and COX-2 inhibitors for management of postoperative pain unless contraindications are present. The use of gabapentinoids is also recommended by both guidelines to be considered. Notably, although antidepressants are used for management of chronic pain syndromes, they are not included in recommendations from these guidelines.

Recommendations are generally similar between ASA guidelines and those from APS/ASRAPM/ASA regarding other pharmacologic analgesics, but greater detail is provided in the joint guideline, particularly regarding opioid therapy.1,6 For example, the joint guideline recommends strongly that oral opioid administration be preferred over IV administration because of a lack of data demonstrating superiority of either route. The guideline also recommends strongly against long-acting (LA) oral opioids because of the need for rapid dose titration and lack of data demonstrating LA formulations are superior.1 If intravenous (IV) opioid administration is necessary, the joint guideline prefers the use of patient-controlled analgesia (PCA) over healthcare provider-initiated intermittent bolus dosing. Intramuscular opioid administration should be avoided because of the risk for pain and unreliable absorption. Lastly, preoperative administration of opioids is not recommended because no studies have demonstrated efficacy in this setting. Further recommendations pertaining to other analgesic classes are provided by the joint guideline, reflecting strength of recommendation and quality of evidence, and are summarized in Table 1.

Beyond these recommendations, guidance for specific medications or surgical procedures are limited in the ASA and APS/ASRAPM/ASA guidelines.1,6 The ASA guideline recommends, however, that doses should be optimized to balance efficacy with adverse events, and the choice of medication, dose, route, and duration of therapy should be tailored to individual patients.

Table 1. APS/ASRAPM/ASA guideline recommendations for non-opioid analgesics used in perioperative MMA regimens.1

Drug

Strength of recommendation

Quality of evidence

Comment

NSAIDs/ acetaminophen

Strong

High
  • Recommended for all adults and children without contraindications for use
  • Combination of acetaminophen and NSAIDs may be more effective than either drug alone
  • Contraindicated in patients undergoing CABG surgery because of increased risk of CV events
  • Evidence does not suggest any clear differences between oral and IV administration of NSAIDs and acetaminophen, other than onset of action

Celecoxib

Strong

Moderate
  • Recommended in adults without contraindications
  • Evidence is insufficient to recommend a preoperative dose, although most common doses are 200 to 400 mg 30 to 60 minutes preoperatively
  • Contraindicated in patients undergoing CABG surgery because of increased risk of CV events

Gabapentin or pregabalin

Strong

Moderate
  • Evidence is insufficient to determine optimal dosing
  • Evidence for use in children is limited

Ketamine

Weak

Moderate
  • Recommended to be considered in adults
  • Evidence is insufficient to recommend optimal dosage regimen, but panel suggests preoperative bolus of 0.5 mg/kg followed by 10 mcg/kg/min intraoperatively, with or without lower-dose postoperative infusion
  • Associated with hallucinations and nightmares
  • May be useful in patients highly tolerant or intolerant of opioids

Lidocaine

Weak

Moderate
  • Recommended to be given IV to adults without contraindications who undergo laparoscopic abdominal surgery
  • Evidence is insufficient to recommend optimal dosage regimen, but the panel suggests an induction dose of 1.5 mg/kg followed by 2 mg/kg/h intraoperatively
  • Postoperative administration has not been well studied

Abbreviations: CABG=coronary artery bypass graft; CV=cardiovascular; IV=intravenous, MMA=multimodal analgesia; NSAID=non-steroidal antiinflammatory drug.

Procedure-specific recommendations

In addition to the ASA and joint guidelines, two additional sets of guidelines are available that provide recommendations specific to individual surgical procedures.7,8 Procedure-specific postoperative pain management (PROSPECT) is an international collaboration composed of anesthesiologists and surgeons and uses procedure-specific evidence and critical expert interpretation to formulate recommendations. Similarly, the Enhanced Recovery After Surgery (ERAS) Society provides guidelines produced by review of available evidence by working groups of experts in the Society, and in some cases, in collaboration with other societies such as The European Society for Clinical Nutrition and Metabolism.4

Clinicians needing to review detailed information on recommendations for MMA regimens for specific procedures may benefit from guideline recommendations by PROSPECT and ERAS, which provide a total of 19 different guidelines.7,8 Advantages of these guidelines include recommendations regarding specific combinations of pharmacologic analgesia for each surgical procedure, which provides more granular recommendations than some of those in the ASA and joint guidelines.

As do PROSPECT and ERAS guidelines, the joint APS/ASRAPM/ASA guideline provides some procedure-specific recommendations on pharmacologic therapy that provide a helpful summary in common surgeries.1 In addition to opioids and NSAIDs, which are generally recommended in the absence of contraindications, IV ketamine and gabapentin or pregabalin are listed as options for components of MMA in thoracotomy, open laparotomy, total hip replacement, total knee replacement, spinal fusion, and coronary artery bypass graft (CABG). Among these surgeries, IV lidocaine may be an option in open laparotomy. Lastly, acetaminophen, but not NSAID therapy, is listed as an option in spinal fusion and CABG.

Non-systemic components of MMA

In addition to systemic analgesic therapy, the ASA and joint guidelines provide recommendations for local and peripheral modalities for postoperative pain control, which are mostly restricted to use in surgeries in which they have shown efficacy.1,6 The joint guideline states that local subcutaneous or intraarticular infiltration of LA anesthetics at the surgical site has been shown to be effective in MMA in several surgeries, although this benefit has not been demonstrated in all surgical settings. For this reason, the recommendation that such therapy be considered in cesarean section, laparotomy, and hemorrhoid surgery is weak, and based on moderate-quality evidence. Similarly, peripheral regional analgesia has demonstrated efficacy in thoracotomy, lower extremity joint surgery, shoulder surgery, cesarean section, and hemorrhoid surgery, and is strongly recommended by the joint guideline in such settings. Peripheral regional analgesia with local anesthetics is recommended to utilize continuous administration when the need for analgesia is likely to exceed the duration of effect of a single injection. Adjuvant clonidine may accompany single-injection peripheral neural blockage in order to prolong the duration of analgesia, although this is a weak recommendation, and the 2-hour prolongation of neural blockade may be offset by increased risk of hypotension, syncope, and sedation. Lastly, neuraxial analgesia is strongly recommended to be routinely considered for major thoracic and abdominal procedures. Based on evidence indicating that epidural or spinal analgesia may decrease the risk of postoperative mortality, venous thromboembolism, myocardial infarction, pneumonia, ileus, and respiratory depression, this recommendation is particularly relevant to patients at risk for complications that are cardiac, pulmonary, or gastrointestinal in nature. Non-pharmacologic components of MMA are only weakly recommended by both guidelines. Although the optimal cognitive method is unknown, they are associated with few harms.14 In contrast, evidence for physical non-pharmacologic methods (eg, acupuncture, cold therapy) is insufficient.

Gaps in Knowledge

Despite recommendations for the use of MMA in many surgical procedures, numerous gaps in knowledge remain, as described in detail by the APS in a separate document related to the production of the joint guideline.14 For example, the variety of surgical procedures, pharmacologic agents, and dosage regimens complicate the identification of the optimal combination of agents and their respective dosages and times of administration. Furthermore, the potential for patient characteristics such as sex, race, ethnicity, and age to modify the effect of MMA requires greater exploration. Further research should also explore outcomes, such as the effect of NSAIDs and other analgesics on healing of bone or soft tissue, and the optimal duration and tapering strategies for opioid treatment after hospital discharge.

Conclusion

Multimodal analgesia, which targets multiple mechanisms of pain, has demonstrated safety and efficacy in a variety of surgical procedures to reduce postoperative pain and reduce exposure to opioids. Guidelines from the ASA and APS/ASRAPM/ASA provide general recommendations on the use of MMA, including for particular drugs and in specific surgeries. More detailed recommendations may be reviewed in the sets of guidelines produced by the PROSPER and ERAS societies. Multimodal analgesia is generally recommended in a variety of different surgeries, but the optimal combination, dosage regimen, and time of administration of pharmacologic therapies require further study.

References

1.         Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131-157.

2.         Mariano ER. Management of acute perioperative pain. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate; 2018. Accessed May 3, 2018.

3.         Schumacher MA, Basbaum AI, Naidu RK. Opioid agonists and antagonists. In: Katzung BG, ed. Basic & Clinical Pharmacology. 14th ed. New York, NY: McGraw-Hill Education; 2017.

4.         Beverly A, Kaye AD, Ljungqvist O, Urman RD. Essential elements of multimodal analgesia in Enhanced Recovery After Surgery (ERAS) guidelines. Anesthesiol Clin. 2017;35(2):e115-e143.

5.         Wick EC, Grant MC, Wu CL. Postoperative multimodal analgesia pain management with nonopioid analgesics and techniques: a review. JAMA Surg. 2017;152:691-697.

6.         American Society of Anesthesiologists Task Force on Acute Pain M. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248-273.

7.         Anonymous. Procedure-specific postoperative pain management (PROSPECT). PROSPECT website. https://www.postoppain.org/. Accessed April 9, 2018.

8.         ERAS Society. ERAS Society guidelines. Enhanced Recovery After Surgery Society website. http://erassociety.org/. Accessed April 12, 2018.

9.         Polomano RC, Fillman M, Giordano NA, Vallerand AH, Nicely KL, Jungquist CR. Multimodal analgesia for acute postoperative and trauma-related pain. Am J Nurs. 2017;117(3 Suppl 1):S12-S26.

10.       Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-Methyl-d-Aspartate (NMDA) receptors in pain: a review. Anesth Analg. 2003:1108-1116.

11.       Gill JS. Peripheral nerve blocks. In: Bajwa ZH, Wootton R, Warfield CA, eds. Principles and Practice of Pain Medicine. 3rd ed. New York, NY: McGraw-Hill; 2018. http://accessanesthesiology.mhmedical.com.proxy.cc.uic.edu/content.aspx?bookid=1845&sectionid=133691483. Accessed May 11, 2018.

12.       Catterall WA, Mackie K. Local Anesthetics. In: Brunton LL, Hilal Dandan R, Knollmann BC, eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2018. http://accesspharmacy.mhmedical.com.proxy.cc.uic.edu/content.aspx?bookid=2189&sectionid=170106799. Accessed May 11, 2018.

13.       Darnall BD, Sturgeon JA. Pain psychology for perioperative and chronic pain management. In: Longnecker DE, Mackey SC, Newman MF, Sandberg WS, Zapol WM, eds. Anesthesiology. 3rd ed. New York, NY: McGraw-Hill; 2018. http://accessanesthesiology.mhmedical.com.proxy.cc.uic.edu/content.aspx?bookid=2152&sectionid=164242672. Accessed Accessed May 11, 2018.

14.       Gordon DB, de Leon-Casasola OA, Wu CL, Sluka KA, Brennan TJ, Chou R. Research Gaps in Practice Guidelines for Acute Postoperative Pain Management in Adults: Findings From a Review of the Evidence for an American Pain Society Clinical Practice Guideline. J Pain. 2016;17(2):158-166.

Prepared by:

Devon Burhoe, PharmD

PGY1 Pharmacy Practice Resident

University of Illinois at Chicago

June 2018

The information presented is current as of April 27, 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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