Propofol is a general anaesthetic agent that is widely used for induction of anaesthesia. It has a rapid onset of action with a dose-related hypnotic effect. Recovery is rapid even after prolonged use [1,2]. However, it causes pain or discomfort at the injection site in 28–90% of patients . A number of techniques have been used to minimize propofol-induced pain with variable results . After reviewing more than 6000 patients in a trial for prevention of propofol injection pain, the most effective method is considered to be the use of a tourniquet and prior injection of lidocaine .
Diphenhydramine is an antihistamine that also has local anaesthetic properties .
There is no reported study to date in the literature that uses diphenhydramine to reduce the prevalence and severity of propofol injection pain. This randomized, double-blind, placebo-controlled study was designed to compare the effectiveness of diphenhydramine and lidocaine on preventing propofol-induced injection pain.
The local Ethics Committee at Selcuk University, Faculty of Medicine, approved the study protocol and informed patient consent was obtained. One hundred and eighty ASA I or II adult patients undergoing elective surgery under general anaesthesia were included in the study. Patients with difficulties in communication or with a history of allergy to diphenhydramine or amide group drugs, diabetes mellitus or cardiac problems and patients who received analgesics or sedative drugs within the 24 h before surgery were excluded from the study.
The patients were visited 1 day prior to surgery and were informed of the study protocol, and the verbal pain rating scale was explained. None of the patients received premedication. On arrival to the anaesthetic room, routine monitoring was applied and a 20-G cannula was inserted into a cephalic vein in the antecubital fossa of the left arm. Patients were randomly allocated into one of the three groups of 60 each. Group I (placebo) received normal saline 2 mL, Group II received lidocaine 2 mL (40 mg) (Aritmal® 2%; Biosel, Istanbul) and Group III received diphenhydramine hydrochloride 2 mL (20 mg) (Benison®; Biosel, Istanbul). Identical syringes containing study drugs were prepared and labelled by a pharmacist not involved in this study.
An independent anaesthetist, who was unaware of group assignments, assessed the intensity of the pain the patients experienced. The study drug was injected over 5 s, while venous occlusion was applied to the upper arm using a rubber tourniquet for 1 min. The occlusion was then released and the patients received one quarter of the total calculated dose of propofol over 5 s. After injecting the first quarter of the propofol dose, the patients were asked verbally to describe the intensity of pain they experienced using a three-point verbal rating scale: 0 = none, 1 = mild pain, 2 = severe pain (also strong vocal response accompanied by facial grimacing, arm withdrawal or tears) . Once the assessment of injection pain was performed, induction of anaesthesia continued according to the anaesthetist’s routine practice. The induction dose of propofol (Pofol® 1%; Dongkook Pharm. Co., Korea) was 2.5 mg kg−1. All drugs were maintained at room temperature and were used within 30 min of preparation. During tourniquet application, intraoperatively and at 24 h after operation, the injection site was examined for pain, oedema, wheal or flare response by the independent anaesthetist. The patients were observed for side-effects and extrapyramidal reactions, such as acute dystonic–dyskinetic reactions for 24 h.
A power study was conducted based on similar previous studies. Assuming that the prevalence of pain after intravenous (i.v.) propofol is 70% and that this would be reduced to 35% after therapy, with α = 0.05 and β = 0.95, 49 patients would need to be included in each group. We therefore included 60 patients in each group. The data were analysed by a team not involved in the previous phases of the study.
Data are expressed as mean (SD) or number. SPSS version 10.0 was used for statistical analysis. One-way ANOVA was used for the comparison of patient characteristics data and the X2-test was used to analyse the prevalence and score of pain during injection of propofol. P < 0.05 was considered as significant.
There were no significant differences in gender, age and weight among the groups (Table 1). The prevalence and the severity of pain in each group are shown in Table 2. Diphenhydramine and lidocaine significantly decreased the frequency and severity of propofol pain when compared with the control group (P < 0.05). However, there was no significant difference between the lidocaine and diphenhydramine groups (P > 0.05). No complications, such as pain, oedema, wheal or flare response, were observed at the injection site and no patient experienced extrapyramidal disturbances after surgery.
To our knowledge, this is the first double-blind, randomized, prospective, placebo-controlled study in which diphenhydramine is used as a local anaesthetic to prevent propofol injection pain. The results of this study indicate that both lidocaine and diphenhydramine prevent the pain caused by propofol injection through an antecubital vein in adults. The concentration of free propofol appears to be the determinant for pain, this concentration being high in lipid solutions [7,8]. Propofol belongs to the group of phenols that can irritate the skin, mucous membrane and venous intimae . It may activate the kallikrein–kinin system and release bradykinin, thereby producing venous dilation and hyperpermeability, which increases contact between the aqueous phase of propofol and free nerve endings resulting in pain on injection .
Because of the high prevalence of pain with the above-proposed mechanisms in mind, numerous methods have been applied to reduce its prevalence and severity. These methods have included adding lidocaine to propofol with or without a tourniquet, cooling or warming, diluting the propofol solution and injection of propofol into a large vein [10–12]. Mixing propofol with lidocaine may have disadvantages as the stability and efficacy of propofol can be impaired and a coalescence of oil droplets may appear [13,14]. Prior to propofol, injection of ondansetron, ketamine, metoclopramide, thiopental, non-steroid anti-inflammatory drugs (NSAIDs), opioids or magnesium sulphate has also been tried with variable results [1,9,15–19]. Among them, i.v. lidocaine with a tourniquet before the propofol injection is considered as the most effective method . It is presumed that lidocaine acts on the pain caused by propofol in two ways, as a local anaesthetic and as a stabilizer for pain mediators . Therefore in this study, lidocaine was selected as the method of treatment to compare the effects of diphenhydramine.
Diphenhydramine is traditionally used as an H1-antagonist, which can be used to treat reactions to anaesthetic drugs and to help prevention of postoperative nausea and vomiting [20,21]. Smith  was the first to describe the successful use of diphenhydramine as a local anaesthetic in dentistry in 1961. It may be a safe alternative to lidocaine in patients with a history of local anaesthetic allergy . One previous open label study exists, which does not appear in the indexed literature and which compares the effectiveness of diphenhydramine for preventing pain on injection of propofol . In that study, 25 mg ketamine and 10 mg diphenhydramine were found to be clinically more effective than 0.5 mg alfentanil and 20 mg ketolorac or placebo in preventing propofol injection pain.
The local anaesthetic properties of diphenhydramine have been attributed to its structural similarities to other local anaesthetic effects and presumably also blocks sodium channels [25–27]. Diphenhydramine 1% was reported to be as effective as lidocaine 1% for achieving dermal local anaesthesia , although with a slower onset of action .
The safety of diphenhydramine is an important issue. There is one case of skin necrosis after subcutaneous injection reported by Dire and Hogan . However, our previous study showed that diphenhydramine is a safe and useful adjunct to lidocaine for i.v. regional anaesthesia and side-effects such as local skin reactions, skin oedema, necrosis or pain were not observed . Because of the above properties, we postulated that diphenhydramine might be an alternative drug to lidocaine in patients who are known to be allergic to local anaesthetics or requiring H1-antagonists. Our study design only aimed to assess the effectiveness and safety of diphenhydramine but did not aim to study its effectiveness on nausea or vomiting.
Diphenhydramine has a number of disadvantages. It is a central nervous system depressant and has anticholinergic properties. Although diphenhydramine is used for the treatment of extrapyramidal side-effects of drugs, there have been seven case reports of acute dystonic reactions occurring after therapeutic doses of diphenhydramine in adults [32–36]. None of our patients experienced extrapyramidal reactions after recovery from anaesthesia.
Injection pain depends on many factors, such as the vein used for injection, size of cannula, age of the patient and rate of injection. Fujii and colleagues  and Agarwal and colleagues  found that the prevalence of pain on injection of propofol into dorsal hand veins is 77% and 78%, respectively. However, Scott and colleagues  reported that injecting into a large vein reduced pain because of the low concentration of propofol due to dilution with blood. Therefore, it was not surprising that we observed a lower prevalence of pain in the control group after the injection of propofol into an antecubital forearm vein than into a dorsal hand vein.
The additional application of a venous tourniquet improves the pain-reducing effect if drugs with a peripheral mechanism of action are used for the prevention of pain, because of increasing local effect of the drug . The venous occlusion method that we used in this study may have contributed to the effectiveness of lidocaine and diphenhydramine, both of which are local anaesthetics.
In conclusion, injection of diphenhydramine with venous occlusion can be considered as an alternative to lidocaine for reducing the prevalence of pain caused by injection of propofol into peripheral veins.
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