NIHR DC Discover

NIHR Signal Pain on injection of a widely used anaesthetic may be reduced if a common anti-sickness drug is given first

Published on 7 June 2016

doi: 10.3310/signal-000249

This review found that giving an anti-sickness drug, like ondansetron, before propofol, an anaesthetic, helped reduce the frequency and severity of injection pain.

The intravenous anaesthetic propofol is used at the start of almost all general anaesthetics in the UK but it does often cause unpleasant pain when it is injected.

This review of trials looked for trials of any drug in the group of commonly-used anti-sickness drugs called 5HT3 receptor antagonists. Ondansetron, one of these drugs, is often used during anaesthesia to reduce nausea and vomiting after waking, but is usually given after the anaesthetic injection.

All eight trials in this review were conducted in Asia on adults. One of the antagonist drugs used (in about 20% of those studied) is not currently available in the UK, reducing direct relevance.

The findings suggest that a simple change in sequence of commonly used drugs could improve patient comfort.

Share your views on the research.

Why was this study needed?

Propofol is the most commonly used intravenous anaesthetic to send people to sleep before surgery in the UK.

Up to 60% of people experience pain at the site of injection and infusion – usually the back of the hand. While this pain is likely to be modest, reducing discomfort could help some people, particularly children, for whom pain is more distressing, and those who have many operations. Other ways of reducing propofol injection pain have been tried, such as warming the drug or mixing it with lidocaine but these don’t work particularly well.

Nausea is a common problem after anaesthesia. Drugs known as 5-HT3 receptor antagonists, such as ondansetron are often used to reduce nausea. This review investigated the effectiveness and safety of 5-HT3 receptor antagonists at reducing propofol injection pain, compared with salt solution control. Some trials compared it to lidocaine.

What did this study do?

This was a systematic review and meta-analysis of eight randomised controlled trials containing 834 adults.

To be included in the review trials needed to assess changes in the incidence and intensity of propofol injection pain between injected 5-HT3 receptor antagonist drugs compared with salt-solution. Four of the eight trials also compared lidocaine against salt solution.

The trial 5-HT3 receptor antagonist drugs were ondansetron (282 patients), granisetron (292 patients), ramosetron (180 patients) and palonosetron (80 patients).

All eight trials were carried out in Asia (Korea, Iran and India). Ramosetron is not currently available in the UK, which somewhat reduces the applicability of the results.

What did it find?

  • Pre-treatment with 5-HT3 receptor antagonist drugs, compared with the control, reduced the likelihood of propofol injection pain by an average of 57% across all eight trials (relative risk 0.43, 95% confidence interval 0.33 to 0.56).
  • In absolute terms 34.1% of those given salt solution reported no pain compared with 77.2% given the drugs.
  • There were no reported differences in side effects, and no patient reported pain or discomfort associated with the 5-HT3 receptor antagonist drug injection.
  • Combined findings from the four trials comparing 5-HT3 receptor antagonist drugs with lidocaine showed no significant difference in likelihood of experiencing propofol injection pain or reducing its severity.

What does current guidance say on this issue?

UK guidance on minimum standards of sedation practice for healthcare was published in 2013. However, there is no guidance specifically on using 5-HT3 receptor antagonist drugs for the purpose of reducing propofol injection pain. Ondansetron, granisetron and palonosetron are currently marketed in the UK as anti-sickness drugs, while ramosetron is not currently licensed in the UK at all. Mixing of lidocaine with propofol, although commonly practiced, is outside the product licence for each drug.

What are the implications?

Using 5-HT3 receptor antagonists to prevent or reduce propofol injection-related pain, on top of their existing use to prevent post-operative sickness and nausea, could be a useful new dual-use. 

Further research should better establish the effectiveness and safety of these drugs in children and other groups in this country at high risk of propofol injection pain.

Citation and Funding

Wang W, Zhou L, Wu L, et al. 5-HT Receptor Antagonists for Propofol Injection Pain: A Meta-Analysis of Randomized Controlled Trials. Clin Drug Investig. 2016;36(4):243-53.

No funding information was provided for this study.

Bibliography

Academy of Medical Royal Colleges. Safe sedation practices for healthcare procedures. Standards and guidance. London: Academy of Medical Royal Colleges; 2013.

Euasobhon P, Dej-arkom S, Siriussawakul A, et al. Lidocaine for reducing propofol-induced pain on induction of anaesthesia in adults. Cochrane Database of Syst Rev. 2016;(2):CD007874.

Why was this study needed?

Propofol is the most commonly used intravenous anaesthetic to send people to sleep before surgery in the UK.

Up to 60% of people experience pain at the site of injection and infusion – usually the back of the hand. While this pain is likely to be modest, reducing discomfort could help some people, particularly children, for whom pain is more distressing, and those who have many operations. Other ways of reducing propofol injection pain have been tried, such as warming the drug or mixing it with lidocaine but these don’t work particularly well.

Nausea is a common problem after anaesthesia. Drugs known as 5-HT3 receptor antagonists, such as ondansetron are often used to reduce nausea. This review investigated the effectiveness and safety of 5-HT3 receptor antagonists at reducing propofol injection pain, compared with salt solution control. Some trials compared it to lidocaine.

What did this study do?

This was a systematic review and meta-analysis of eight randomised controlled trials containing 834 adults.

To be included in the review trials needed to assess changes in the incidence and intensity of propofol injection pain between injected 5-HT3 receptor antagonist drugs compared with salt-solution. Four of the eight trials also compared lidocaine against salt solution.

The trial 5-HT3 receptor antagonist drugs were ondansetron (282 patients), granisetron (292 patients), ramosetron (180 patients) and palonosetron (80 patients).

All eight trials were carried out in Asia (Korea, Iran and India). Ramosetron is not currently available in the UK, which somewhat reduces the applicability of the results.

What did it find?

  • Pre-treatment with 5-HT3 receptor antagonist drugs, compared with the control, reduced the likelihood of propofol injection pain by an average of 57% across all eight trials (relative risk 0.43, 95% confidence interval 0.33 to 0.56).
  • In absolute terms 34.1% of those given salt solution reported no pain compared with 77.2% given the drugs.
  • There were no reported differences in side effects, and no patient reported pain or discomfort associated with the 5-HT3 receptor antagonist drug injection.
  • Combined findings from the four trials comparing 5-HT3 receptor antagonist drugs with lidocaine showed no significant difference in likelihood of experiencing propofol injection pain or reducing its severity.

What does current guidance say on this issue?

UK guidance on minimum standards of sedation practice for healthcare was published in 2013. However, there is no guidance specifically on using 5-HT3 receptor antagonist drugs for the purpose of reducing propofol injection pain. Ondansetron, granisetron and palonosetron are currently marketed in the UK as anti-sickness drugs, while ramosetron is not currently licensed in the UK at all. Mixing of lidocaine with propofol, although commonly practiced, is outside the product licence for each drug.

What are the implications?

Using 5-HT3 receptor antagonists to prevent or reduce propofol injection-related pain, on top of their existing use to prevent post-operative sickness and nausea, could be a useful new dual-use. 

Further research should better establish the effectiveness and safety of these drugs in children and other groups in this country at high risk of propofol injection pain.

Citation and Funding

Wang W, Zhou L, Wu L, et al. 5-HT Receptor Antagonists for Propofol Injection Pain: A Meta-Analysis of Randomized Controlled Trials. Clin Drug Investig. 2016;36(4):243-53.

No funding information was provided for this study.

Bibliography

Academy of Medical Royal Colleges. Safe sedation practices for healthcare procedures. Standards and guidance. London: Academy of Medical Royal Colleges; 2013.

Euasobhon P, Dej-arkom S, Siriussawakul A, et al. Lidocaine for reducing propofol-induced pain on induction of anaesthesia in adults. Cochrane Database of Syst Rev. 2016;(2):CD007874.

5-HT Receptor Antagonists for Propofol Injection Pain: A Meta-Analysis of Randomized Controlled Trials

Published on 11 February 2016

Wang, W.,Zhou, L.,Wu, L. X.,Wang, T.,Zhang, C. B.,Sun, L.

Clin Drug Investig , 2016

BACKGROUND AND OBJECTIVES: 5-hydroxytryptamine3 (5-HT3) receptor antagonists have been commonly used to reduce propofol injection pain. The aim of this meta-analysis was to evaluate the efficacy and safety of 5-HT3 receptor antagonists in decreasing the incidence and intensity of propofol injection pain. METHODS: Online databases of Pubmed, Embase and the Cochrane Central Register of Controlled Trials were searched as well as reference lists of included studies and recent reviews. Eligible randomized controlled trials (RCTs) assessing the efficacy and safety of 5-HT3 receptor antagonists for propofol injection pain were identified. The outcomes included the incidence and intensity of propofol injection pain and adverse effects. We calculated risk ratios (RR) with 95 % confidence intervals (CIs) for dichotomous data and adopted fixed or random-effects model when proper. RESULTS: A total of eight RCTs were included in the final analysis. Compared with the control group, 5-HT3 receptor antagonists were related to a decreasing incidence of propofol injection pain (RR 0.43, 95 % CI 0.33-0.56, P < 0.05). Besides, they also effectively alleviated the severity of propofol injection pain. They significantly reduced the number of patients with moderate (RR 0.21, 95 % CI 0.15-0.30, P < 0.05) and severe pain (RR 0.16, 95 % CI 0.10-0.25, P < 0.05) during propofol injection. 5-HT3 receptor antagonists and lidocaine were equally effective in preventing propofol injection pain. Moreover, only one article mentioned the adverse effects of 5-HT3 receptor antagonists in two patients. CONCLUSION: Our meta-analysis indicates that 5-HT3 receptor antagonists can effectively reduce the incidence and severity of propofol injection pain. Additionally, 5-HT3 receptor antagonists may become the alternatives to lidocaine in attenuating propofol injection pain. However, evidence is still limited for the safety of 5-HT3 receptor antagonists on propofol injection pain.

Expert commentary

Although the analysis is robust, there are some points of caution. One is that although pain on injection is quite common, it is a relatively modest side effect in comparison with so many others that we are still tackling in relation to anaesthesia. Second, is that whereas statistical effects are provided, actual effect sizes are not. So we know treatment is statistically significant but we are none the wiser as to by how much the pain is reduced. This is compounded by all the studies employing only a 4-point rather than a 10 point scale for the pain. This may be the norm, but it reflects how mild and short-lived the pain actually is. Nevertheless, with the very good side effect profile of 5HT3 drugs and their use already as antiemetics, this intervention has potential.

Professor Jaideep Pandit, Consultant Anaesthetist, Nuffield Department of Anaesthetics, Oxford University Hospitals NHS Trust & Fellow, St John's College, Oxford

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