Anesthesiology, Article

RETRACTED: Sublingual buprenorphine versus intravenous or intramuscular morphine in acute pain: A systematic review and meta-analysis of randomized control trials

a b s t r a c t

Intro: Buprenorphine is a potent analgesic agent with several unique and favourable features such as its sublin- gual formulation. The aim of this study is to compare the effectiveness of sublingual versus intramuscular and in- travenous buprenorphine in acute pain.

Methods: Five major databases were systematically searched until April 2018. All randomized control trials com- paring sublingual buprenorphine with intravenous or intramuscular morphine in acute pain were included in this review. These studies were assessed for Level of evidence and risk of bias. The data was then analyzed both qualitatively and where appropriate by meta-analysis. The primary outcomes were analgesic effect up to six hours and Rescue analgesia requirement. The secondary outcomes were incidence of respiratory depression, nausea, vomiting, dizziness and hypotension.

Results: Nine studies comparing sublingual and intramuscular or intravenous buprenorphine were identified and included 826 patients. There was no difference in pain at any time point before six hours or need for rescue analgesia between the two agents. There was no difference in secondary outcomes between the two agents.

Discussion: Sublingual buprenorphine offers an effective alternative to intravenous or intramuscular analgesia in acute pain. Sublingual buprenorphine appears to be a viable option in patients where intravenous access is diffi- cult or not favourable.

(C) 2018

  1. Introduction

The United States is currently experiencing an opioid overdose epidemic with a strong correlation between opioid prescribing and overdose related deaths [1]. Recent Emergency Department (ED) litera- ture has provided a strong focus on the use of non-opioid analgesic op- tions [2]. A recent study by Jeffery and Colleagues (2018) showed that opioid prescribing to naive patients from the ED carries a lower risk of longer-term opioid use than from other acute settings [3]. Nonetheless improvements to opioid prescribing in ED can undoubtedly be obtained. Acute pain requiring Opioid analgesia is common in the ED and a considered choice of opiate agent is warranted. For example, agents such as oxycodone and hydromorphone have been linked with an in-

creased propensity for the development of long-term addiction [4].

* Corresponding author.

E-mail address: [email protected] (R. Vlok).

In recent years there has been a shift in the understanding of the clinical effect of buprenorphine. Buprenorphine is well known for its utility in the management of Opioid use disorders (OUDs), however many recent studies have demonstrated its efficacy in the setting of acute pain management [5]. Buprenorphine possess a number of bene- fits including is analgesic benefits, agonist-antagonist pharmacodynam- ics which antagonizes the reward pathway and its somewhat unique formulations [6].

Buprenorphine is available in a number of formulations, including sublingual (SL). SL formulations have a number of practical benefits. Patients in whom Intravenous access are difficult to obtain, in Bowel obstructions where oral opioids are contraindicated, where IV lines are being minimized or in palliative care may benefit from SL formulations of analgesia. The purpose of this systematic review and meta-analysis is to compare the Analgesic efficacy and time of onset of SL versus IV or intramuscular buprenorphine.

https://doi.org/10.1016/j.ajem.2018.05.052

0735-6757/(C) 2018

  1. Methods
    1. Search strategy

Medline, Cochrane trials registry, SCOPUS, CINAHL and Web of Sci- ence were systematically searched from the inception of the databases until April 2018. This search was conducted by two independent re- viewers (LW & RV) searching the terms (1) ‘buprenorphine’ AND ‘acute pain’; (2) ‘buprenorphine’ AND ‘Emergency Department’

(3) ‘buprenorphine’ AND ‘post-operative pain’. A manual reference check and citation check of included papers was performed via Google Scholar to identify any additional studies.

Study eligibility

Included studies were required to report on the use of sublingual buprenorphine versus IV or IM morphine in the management of acute pain in the ED or inpatient hospital setting. Studies investigating the use of buprenorphine in those with pre-existing chronic pain or on opioid substitution programs were excluded. Animal studies and non-clinical studies were excluded. Only Randomized controlled trials were eligible for inclusion and there were no language criteria for exclusion. Two reviewers (LW and RV) independently assessed each study for inclusion in this systematic review.

Data extraction

The data from each article was independently extracted by two re- viewers (LW and GA). The data extracted from each study included the study design, patient characteristics and clinical outcome results. The data collected by each reviewer was then compared for homogeneity.

Clinical outcome measures

Our primary outcomes of interest were analgesic effect (as mea- sured by Visual analogue scale) and rescue analgesia requirement. The secondary outcomes were incidence of respiratory depression, sedation, nausea, vomiting, rescue analgesia, dizziness and hypotension and time to first analgesia.

Level of evidence, risk of bias & outcome level of evidence ranking

Each article was evaluated using the Centre for Evidence Based Med- icine (CEBM): Levels of Evidence Introduction Document [7]. These studies were then assessed for risk of bias and methodological quality using the Cochrane Collaboration’s tool for assessing the risk of bias [8]. The results from each study were then grouped into individual out- comes. Due to the anticipated inconsistencies in outcome reporting measures both Qualitative and quantitative analyses were performed. The qualitative analysis was conducted by grouping outcomes and then assigning a level of evidence ranking based on the collective strength of evidence [8].

  1. Strong Evidence: Two or more high quality (quality score >=4) Randomized controlled trials with >=75% consistency in findings.
  2. Moderate Evidence: One high quality RCT and two or more low qual- ity studies with >=75% consistency in findings.
  3. Limited Evidence: One high quality RCT or multiple low quality stud- ies with >=75% consistency in findings.
  4. Conflicting Evidence: Multiple low and/or high quality studies with

<=75% consistency in findings.

  1. No Evidence: No studies could be found, may include technique reports
    1. Statistical analyses

The combined data was analyzed using RevMan 5.3 software (The Nordic Cochrane Centre, Copenhagen, Denmark), using the odds ratio (OR) with 95% confidence interval (CI) for dichotomous outcomes, and the Weighted mean difference with 95% CI for continuous outcomes. The Mantel-Haenszel (M-H) random effects model was used. Heterogeneity was assess using the I2 statistic, with an I2 N 50% in- dicating significant heterogeneity. P value of b0.05 provided evidence of significant OR and WMD. A P value of b0.10 was used to demonstrate heterogeneity of intervention effects.

Reporting

This study was reported in line with PRISMA guidelines [9].

  1. Results
    1. Literature search results

The initial systematic literature search yielded 2365 citations and a fur- ther 15 citations were identified through a manual citation and reference search of relevant articles (Fig. 1). Following the removal of duplicates, an- imal studies, review articles and non-clinical studies, 380 citations remained. These citations were screened based on title. Of these, 90 ab- stracts were screened and 55 full texts were retrieved for review. Nine ar- ticles met the inclusion criteria (Fig. 1) [10-18]. These nine studies included 826 patients (Table 1). Each study was then screened for risk of bias and methodological quality using the Cochrane Collaboration’s tool for assessing the risk of bias (Fig. 2). Four studies met the criteria for high quality RCTs, the remaining five studies were of low quality.

Primary outcomes

Pain was measured using a variety of endpoints including various pain scores and at varioUS time intervals. Eight studies used pain as an end point (Fig. 3). The data was analyzed in four Time groups, namely at less than 1 h, 1 h, 3 h and 6 h. Qualitatively there was no difference in pain between pa- tients who had received SL buprenorphine compared to morphine within the first hour. Quantitative analysis was performed using Visual Analogue Scale . At 1 h there was no difference in pain between the two

Fig. 1. Literature search.

Table 1

Study characteristics.

[18]

Study

No pts. (buprenorphine: morphine)

Mean age (buprenorphine: morphine)

Mean weight (buprenorphine: morphine) (kg unless stated otherwise)

Intervention

Setting

Outcomes

Cuschieri

39:41

58 +- 14: 52 +- 15

63 +- 13: 63 +- 10

Intramuscular morphine 10 mg versus

Abdominal

1. Pain

et al. [10]

buprenorphine 0.3 mg intramuscular

surgery

2. Respiratory

followed by sublingual buprenorphine

depression

0.4 mg. Repeated dosing.

3. Sedation

4. Nausea

5. Vomiting

Edge et al.

49:52

43.8 +- 12.63: 44.6 +-

67.1 +- 8.53: 65.7 +- 8.65

Sublingual buprenorphine 0.4 mg versus

Major surgery

1. Pain

[11]

15.41

intramuscular morphine 10 mg. Single

2. Respiratory

dose.

depression

3. Nausea

4. Vomiting

5. Sedation

Ellis et al. [12]

35:36

Cholecystectomy 51.3

Cholecystectomy 64.3 +- 3.6:

Sublingual buprenorphine 0.4 mg versus

Abdominal

1. Pain

+- 4.3: 53.7 +- 3.5;

66.9 +- 2.1; Herniorrhaphy

intramuscular morphine 10 mg IM.

surgery

2. Sedation

Herniorrhaphy 51.7 +-

72.0 +- 2.1: 75.5 +- 2.3

Repeat dosing.

2.7: 54.7 +- 2.5

Gaitini et al.

26:26

Not stated

Not stated

Sublingual Buprenorphine 0.4 mg versus

Prostatectomy

1. Pain

[13]

1 mg Morphine PCA. Repeat dosing.

  1. Hypotension
  2. Respiratory

depression

Hosseininejad

101:102

40.50 +- 13.50: 39.85 +-

Not stated

2 mg sublingual buprenorphine versus

Emergency

1. time to analgesia

et al. [14]

13.66

Intravenous morphine 0.1 mg/kg. Single

Department:

2. Pruritus

dose.

Renal Colic

Jalili et al. [15]

49:50

35 +- 13: 35 +- 13

Not stated

Buprenorphine 0.4 mg sublingual versus

Emergency

1. Pain

Morphine 5 mg intravenous. Single dose.

Department:

2. Nausea

Acute Pain

3. Dizziness

4. Hypotension

5. Respiratory

depression

Payandemehr

37:32

35 +- 10: 31 +- 10

Not stated.

Sublingual buprenorphine 2 mg versus

ED Renal Colic

1. Pain

et al. [16]

Intravenous Morphine 0.1 mg/kg. Single

2. Nausea

dose.

3. Vomiting

4. Dizziness

5. Hypotension

6. Respiratory

depression

7. Pruritus

8. Sedation

9. Rescue analgesia

Soltani et al.

45:45

39.7 +- 18.0:35.8 +- 15.2

Not stated.

Sublingual buprenorphine 4.5 ug/kg vs

Closed

1. Pain

[17]

intravenous morphine 0.2 mg/kg. Single

dose.

reduction

orthopaedic

  1. Pruritus
  2. Nausea

surgery

4. Vomiting

5. Hypotension

Weiss & Ritz

30:31

Not stated.

Not stated.

Sublingual buprenorphine 4.5 ug/kg vs

Emergency

1. Pain

intravenous morphine 0.2 mg/kg. Single dose.

Department: Acute Myocardial Infarction

  1. Respiratory depression
  2. Nausea
  3. Vomiting

patient groups (WMD = 0.36; 95% CI = -0.32-1.05; I2 = 94%; P = 0.30).

At 3 h two high quality studies showed significant improvement in pain using buprenorphine as opposed to morphine (WMD 0.36; 95% CI =

-0.32-1.05; I2 = 93%; P b 0.001). At 6 h two high quality studies reported pain was significantly improved with buprenorphine compared to mor- phine (WMD = -1.37; 95% CI = -2.05 to -0.68; I2 = 94%; P = 0.008).

Secondary outcomes

  1. Respiratory depression

Six studies investigated respiratory depression via a variety of end- points including incidence of respiratory depression (RR b 10), PaCO2 and mean respiratory rate. Of these three were high quality and three were low quality studies. Quantitative analysis showed no difference between sublingual buprenorphine and morphine (WMD = 0.81; 95%

CI = 0.31-2.17; I2 = 0; P = 0.38) (Fig. 4).

Four studies investigated the incidence of vomiting. No difference was found in incidence of vomiting between patients receiving sublingual buprenorphine or morphine (WMD 0.95; 95% CI = 0.48-1.89; I2 = 0%;

P = 0.89) (Fig. 5). Five studies found no difference in the incidence of nausea between buprenorphine and morphine (WMD 0.86; 95% CI = 0.55-1.35; I2 = 0%; P= 0.52) (Fig. 6).

Hypotension

Four studies investigated the incidence of hypotension. Three were high quality studies and one was a low quality study. Quantitative anal- ysis showed no difference between the two agents (WMD = 0.49; 95% CI = 0.10-2.34; P = 0.37) (Fig. 7).

Dizziness

Two high quality papers reported the incidence of dizziness and found no difference (WMD = 1.29; 95% CI = 0.29-5.78; I2 = 77%; P

= 0.74) (Fig. 8).

Rescue analgesia and time to first analgesia

One study reported on time to first analgesia and demonstrated no difference between the two agents [14]. One study reported on rescue

Fig. 2. Risk of bias summary.

analgesia and reported no difference in the incidence of rescue analgesia use (WMD = 2.34; 95% CI = 0.42-13.01; P = 0.33) [16].

Subgroup analysis: low dose sublingual buprenorphine versus IV or IM morphine

Two studies reported using 2 mg SL buprenorphine [14,16] and seven studies reported lower doses. Subgroup analysis of lower dose buprenorphine was performed.

Pain as measured by VAS was assessed for lower dose buprenorphine only. At less than 1 h, no difference was noted in pain (WMD = -0.04; 95% CI = -0.77-0.70; I2 = 99%; P = 0.92). Pain

measured at one to six hours post administration found no difference, with the confidence intervals crossing the null value (WMD = -0.95; 95% CI = -1.92-0.02; I2 = 99%; P = 0.02). No significant differences were noted in incidence of respiratory depression (OR = 1.67; 95% CI = 0.20-13.89; I2 = 0%; P = 0.63) or vomiting (OR = 0.91; 95%

CI = 0.42-1.94; I2 = 0%; P= 0.8).

There was insufficient data was available to assess differences be- tween hypotension, dizziness, nausea, pruritis and time to first rescue analgesia. There was also insufficient data to group perform a subgroup analysis of the two studies examining the use of 2 mg SL buprenorphine.

  1. Discussion

This is the first systematic review to compare the Clinical effectiveness of sublingual buprenorphine with intravenous or intramuscular morphine in the setting of acute pain management. Nine RCTs with 826 patients were included in this review. Included in this review were four ED studies and five post-surgery studies. Our review was in keeping recent studies, which showed that buprenorphine has similar analgesic and adverse effect properties as intravenous or intramuscular morphine [5,19].

Alongside methadone, buprenorphine is most well known for its role in the management of OUD [20]. Under certain circumstances buprenorphine is known to be the safer of the two agents in treating opi- oid dependence [20]. This was initially thought to be due to its partial agonist-antagonist activity, which was also the reason why buprenorphine has been relatively under-utilized in the setting of acute pain. It is now well known that buprenorphine is approximately 33 times more potent than morphine, with no clinically observable ceiling effect in regards to an- algesia [19,21]. The present study demonstrates an interesting analgesic profile in contrast to well-validated pharmacokinetic studies [22]. Sublin- gual buprenorphine produced a significant analgesic effect, much faster than expected. Overall, sublingual buprenorphine produced equivalent analgesia to morphine at three time points within the first hour of dosing [11,15-17]. Beyond an hour buprenorphine due to its slower elimination kinetics produced a significantly greater analgesic effect than intravenous morphine [22]. Time to first analgesia was only reported in one study, which demonstrated no difference between the SL buprenorphine and IV morphine in emergency department presentations of renal colic [14].

Ideal dosing buprenorphine in acute pain remains to be clarified. At 1 to 6 h, pain was significantly improved in the cohort that included the two studies utilizing 2 mg dosing. No difference was noted at 1 to 6 h between buprenorphine and morphine when these two studies were excluded in subgroup analysis. Subgroup analysis of lower dose buprenorphine investigating incidence of respiratory depression and vomiting showed no difference compared to IM or IV morphine. Insuffi- cient data was available to determine the association with other adverse effects. The 2 mg dose of buprenorphine may therefore provide better analgesia, in keeping with its proposed lack of clinical ceiling effect for analgesia. However, the Adverse effect profiles of higher dose versus lower dose sublingual buprenorphine relative to morphine cannot be adequately described based on current available literature. This would be an important factor to assess in any future research.

It is also worth noting that buprenorphine displayed a similar clinical adverse effect profile to morphine in regard to respiratory depression, sedation, hypotension, nausea and vomiting. This is contrary to well- publicized data showing a ceiling effect on respiratory depression and sedation [19]. This variation is likely related to the multimodal analgesic strategies implemented in most emergency departments as well as a much more diverse sample population, which include elderly patients with Multiple comorbidities. Therefore, caution is advised when using buprenorphine in the acute setting.

In addition to the outcomes investigated in this review there are sev- eral well-documented advantages of sublingual buprenorphine. This in- cludes the well-described kappa antagonism, which has been linked to both euphoric and dysphoric side effect [21]. This is an important con- sideration when using opioids in patients at high risk of developing an opioid addiction [1]. Furthermore, buprenorphine’s non-renal metabo- lism makes it a safe long acting alternative in the setting of renal failure. There are several limitations to this review including the small co- hort of patients and the diversity of settings and study populations. There was also a lack of homogeneity in regard to the tools used to measure certain outcomes such as analgesic effect and respiratory de- pression. It is also worth noting that the majority of studies were under- powered to adequately detect the incidence of most adverse outcomes.

  1. Conclusion

In conclusion, sublingual buprenorphine is an effective alternative to intravenous or intramuscular morphine in adult patients with acute pain. Sublingual buprenorphine appears to be of greatest benefit in patients in whom Intravenous access is difficult to obtain, in bowel obstructions where oral opioids are contraindicated or where IV lines are being mini- mized. Ideal dosing of sublingual buprenorphine remains to be clarified and is an important area of future research. Caution is advised given that buprenorphine displays the same clinical adverse effect profile as other opioids in regards to the risk of respiratory depression and sedation.

Fig. 3. Pain.

Fig. 4. Respiratory depression.

Fig. 5. Vomiting.

Fig. 6. Nausea.

Fig. 7. Hypotension.

Fig. 8. Dizziness.

References

  1. Schuchat, Houry. New data on opioid prescribing in the United States. JAMA 2018. https://doi.org/10.1001/jama.2017.8913, Published Online: July 6, 2017.
  2. Duncan, et al. Alternatives to opioids for pain management in the emergency de- partment decreases opioid usage and maintains patient satisfaction. Am J Emerg Med 2019;37:38-44.
  3. Jeffery, et al. Opioid prescribing for opioid-naive patients in emergency departments and other settings: characteristics of prescriptions and association with long-term use. Ann Emerg Med 2018;71(3):326-336.e19. https://doi.org/10.1016/j. annemergmed.2017.08.042, Epub 2017 Sep 26.
  4. Brat, et al. Postsurgical prescriptions for opioid naive patients and association with overdose and misuse: retrospective cohort study. BMJ 2018;360:j5790.
  5. White, et al. Efficacy and adverse effects of buprenorphine in acute pain: systematic review and meta-analysis. Br J Anaesth 2018;120(4):668-78. https://doi.org/10. 1016/j.bja.2017.11.086.
  6. Kress. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain 2009;13(3):219-30. https://doi.org/10.1016/j.ejpain. 2008.04.011.
  7. Howick J, Chalmers I, Glasziou P, Greenhalgh T, Heneghan C, Liberati A, Moschetti I, Phillips B, Thornton H. The 2011 Oxford CEBM levels of evidence (introductory doc- ument). Oxford Centre for Evidence-Based Medicine; 2011. http://www.cebm.net/ index.aspx?o=5653, Accessed date: 4 September 2018.
  8. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA, Cochrane Bias Methods G, Cochrane Statistical Methods G. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928. https://doi.org/10.1136/bmj.d5928.
  9. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: expla- nation and elaboration. PLoS Med Jul 21 2009;6(7):e1000100.
  10. Cuschieri RJ, Morran CG, McArdle CS. Comparison of morphine and sublingual buprenorphine following abdominal surgery. Br J Anaesth Jan 1 1984;56(8):855-9.
  11. Edge WG, Cooper GM, Morgan M. Analgesic effects of sublingual buprenorphine. An-

aesthesia May 1 1979;34(5):463-7.

  1. Ellis R, Haines D, Shah R, Cotton BR, Smith G. Pain relief after abdominal surgery–a comparison of im morphine, sublingual buprenorphine and self-administered iv pethidine. Br J Anaesth Apr 1 1982;54(4):421-8.
  2. Gaitini L, Moskovitz B, Katz E, Vaisberg A, Vaida S, Nativ O. Sublingual buprenorphine compared to morphine delivered by a patient-controllED analgesia system as post- operative analgesia after prostatectomy. Urol Int 1996;57(4):227-9.
  3. Hosseininejad M, Khaje Samakoush A, Montazer H, Goli Khatir I, Jahanian F, Amini Ahidashti H, Bozorgi F, Yazdani Charati J, Asgarirad H. Comparing the effects of sub- lingual buprenorphine and intravenous morphine on acute renal colic. J Mazandaran Univ Med Sci Dec 15 2016;26(143) (1-0).
  4. Jalili M, Fathi M, Moradi-Lakeh M, Zehtabchi S. Sublingual buprenorphine in acute pain management: a double-blind randomized clinical trial. Ann Emerg Med Apr 1 2012;59(4):276-80.
  5. Payandemehr P, Jalili M, Davani BM, Dehpour AR. Sublingual buprenorphine for Acute renal colic pain management: a double-blind, randomized controlled trial. Int J Emerg Med Dec 1 2014;7(1):1.
  6. Soltani G, Khorsand M, Shamloo AS, Jarahi L, Zirak N. Comparison of intravenous morphine with sublingual buprenorphine in management of postoper- ative pain after closed reduction orthopedic surgery. Arch Bone Jt Surg Oct 2015;3 (4):280.
  7. Weiss P, Ritz R. Analgesic effect and side-effects of buprenorphine in acute coronary heart disease. A randomized double-blind comparison with morphine. Anasth Intensivther Notfallmed Dec 1988;23(6):309-12.
  8. Dahan A, et al. Comparison of the Respiratory effects of intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth 2005;94(6):825-34.
  9. Zedler BK, Mann AL, Kim MM, Amick HR, Joyce AR, Murrelle EL, Jones HE. Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: a systematic review and meta-analysis of safety in the mother, fetus and child. Addiction 2016;111:2115-28. https://doi.org/10.1111/add.13462.
  10. Flood P, Rathmell JP, Shafer S. Stoelting’s pharmacology and physiology in anesthetic practice. Lippincott Williams & Wilkins; 2015.
  11. Bullingham R, McQuay H, Dwyer D, Allen M, Moore R. Sublingual buprenorphine used postoperatively: clinical observations and preliminary pharmacokinetic analy- sis. Br J Clin Pharmacol 1981;12:117-22. https://doi.org/10.1111/j.1365-2125.1981. tb01189.x.

Leave a Reply

Your email address will not be published. Required fields are marked *