Reducing propofol injection pain by pretreatment with tramadol and butorphanol: Are they safe?

Sir,

We read with interest the article entitled “Efficacy of tramadol and butorphanol pretreatment in reducing pain on propofol injection: A placebo-controlled randomized study” by Singh et al.[1. First, we would like to congratulate the authors for their rigorous scientific method. They have presented a very interesting topic, particularly for anesthesiologist. Most patients describe the first stage of their anesthesia as the most troubling part.

The authors conducted prospective, three groups, double-blind, randomized controlled trial on a total of ninety patients scheduled for elective surgery under general anesthesia with propofol. The control group (Group I) received an injection of normal saline 3 ml intravenously (IV). They compared the effect of two interventions on propofol injection pain (PIP) include injection of tramadol 50 mg (Group II) or butorphanol 1 mg IV (Group III). The outcome variables, PIP, were measured using a visual analog scale. Based on their results, the severity of PIP was significantly decreases in Group II and III in comparison to the control group. They reported no side effects for the pretreatment drugs.

Propofol, a common anesthetic agent for induction, often causes pain at injection site, particularly when injected into peripheral distal veins such as dorsum of the hands. The prevalence of PIP has been reported differently in various studies from 28% to 90%. The exact mechanism for PIP is unclear. It has been demonstrated IV injection of propofol irritates internal layer of the venous, which in turn releases the inflammatory mediators such as bradykinin. These mediators dilate venous, and increase its permeability and consequently, stimulate nociceptors and nerve endings.[234] In this regard, Scott et al.[5] proposed the possible role of the plasma kallikrein–kinin system (KKS) to produce PIP. Based on these mechanisms, recently, several preventive and therapeutic methods have been recommended for reducing that pain including using the antecubital vein, cooling, warming or diluting the propofol solution, pretreatment with lidocaine, addition of lidocaine, concomitant administration of lidocaine with propofol, reducing the pH of the propofol, use of thiopental, ephedrine, ondansetron, metoclopramide, nafamostat mesilate, opioids, ketamine, and so forth.[2678] The results of a systematic review, in 2000, revealed pretreatment with lidocaine as the most useful intervention for PIP reduction.[8] This result was confirmed in a more recent systematic review, in 2011, which suggested that lidocaine-propofol admixture is similar to pretreatment with lidocaine in term of PIP reduction.[2]

In these regards, we have some concerns regarding the study conclusion drawn by the authors. Considering the aforementioned mechanisms of action, can Tramadol and/or Butorphanol inhibit or modify the activity of the KKS system. In fact, since the systematic review, in 2000,[8] the pretreatment with lidocaine was widely adopted and still remains the choice of treatment for alleviating PIP due to the nerve ends paralyzing. Future studies should also determine the mechanism of action for their proposed intervention.

As authors reported, a tourniquet was applied about 2 min. Although the location of securing the tourniquet is unclear, the safety of blood stasis following tourniquet needs critical attention. Therefore, the safe time and duration of securing the tourniquets warrant further research. As reported by authors, an IV line was secured in a peripheral vein on the dorsum of the hand. There is well-established evidence that claims about the pain of dorsum of the hand when injecting the propofol.[9] The risk for extravasation and infiltration is increased when the dorsum vessels of the hand were used for injection. For the safety of patients, future PIP reductive interventions studies must consider other sites of IV access such as antecubital site.

Several demographic and clinical factors affect the severity of PIP including the propofol solution pH, the younger age patients, a distal and/or proximal peripheral IV site, the pushing speed of solution into IV line, female gender, and so forth.[3] Singh et al. need to clearly elaborate on the methodology of controlling these variables or their effect on the findings of the study by multivariate analysis. There is a a critical need to use the univariate and multivariate analyses in future researches to find out more factors contributing to the PIP.

Thus to conclude the study by Singh et al. is remarkable and examines significant issues of anesthesia. Certainly, more rigorous clinical trials are needed to understand the potential effects of opioids on pain reduction as well as to find the contributing factors to the PIP. We recommend that future trials will consider the mechanism of action, site of IV access, factors contributing to the PIP, patient gender, and age, procedure's duration, and side effect when designing interventional modalities.

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Conflicts of interest

There are no conflicts of interest.