Propofol is a commonly preferred anesthetic agent due to its rapid induction and recovery characteristics, but injection pain incidence due to propofol is unpleasantly high.1
Hormonal, physical and psychological changes occur in women during the reproductive period due to the menstrual cycle.2 Anesthetic, postoperative analgesic and antiemetic consumptions may vary due to the different stages of the menstrual cycle.3–5 Although, the perception of pain changes during the menstrual cycle in animals, the effects of the menstrual cycle on the perception of pain in humans has not been understood yet.2 However, no studies exist about the effects of the phases of the menstrual cycle on propofol pain. The hypothesis in our study is that propofol injection pain may change in the different phases of the menstrual cycle.
This prospective, randomized and double-blind study aims to evaluate the effects of the follicular and luteal phases of the menstrual cycle on propofol injection pain.
After obtaining the approval of the Hospital Ethics Committee of the Zonguldak Karaelmas University School of Medicine and written informed consents, 72 female patients, 18–49 years old (ASA physical status I–II) and scheduled to undergo elective surgery were enrolled in the study. Exclusion criteria were the presence of neurological or psychiatric diseases, difficulty of communication, history of combined oral contraceptive medication, irregular menstrual cycle, amenorrhoea, previous total abdominal hysterectomy and/or bilateral salphingoopherectomy, pregnancy, renal or hepatic insufficiency and hypersensitivity to the study drugs.
Patients were allowed to receive 0.07 mg kg−1 of midazolam intramuscularly 1 h before the induction of anaesthesia. On arrival in the operating room, patients were instructed on a 10-point numeric rating scale. A 20-gauge intravenous cannula was inserted into a vein on the dorsum of the hand for administration of the study drugs.
The patients were assigned into two groups according to their menstrual phase. The patients who were on the 8–12th day after the first day of the last menstruation were considered to be in the follicular phase of the cycle and assigned to Group F. Those on the 20–24th day after the first day of the last menstruation were considered to be in the luteal phase of the cycle and assigned to Group L.
All study drugs were maintained at room temperature and were used within 30 min.
Another anaesthesiologist, who was unaware of the study groups, assessed the intensity of pain after propofol (Propofol Lipuro 1%, B. Braun Melsungen AG, Germany) injections.
After standard anaesthesia monitorization, 25% of (2.5 mg kg−1) total propofol dose was injected over 20 s. The patients were observed and asked immediately whether they had pain in the arm.
Statistical Package for the Social Sciences 10.0 was used for data analysis. Descriptive statistics for continuous variables were given in mean ± SD. One-way ANOVA was used for age, body weight and propofol injection pain. P less than 0.05 was considered statistically significant.
There were no significant differences in terms of patient characteristics (P > 0.05) (Table 1). The mean propofol pain score was found 1.81 ± 2.30 in Group F and 4.83 ± 3.09 in Group L. Group L was found to have higher propofol injection pain scores than Group F (P < 0.001) (Fig. 1).
In this study, we demonstrated that injection pain scores of propofol were higher in the lutheal phase of the menstrual cycle.
Propofol causes pain or discomfort on injection in a wide range from 28 up to 90% of patients.1,6 Propofol formulated in medium-chain and long-chain triglycerides (MCTs/LCTs) is thought to cause less pain than propofol formulated in LCTs.6 Because of that reason and ethical concerns, we have chosen to use propofol formulated in MCTs/LCTs combination.
Although many studies have been done on reduction of propofol-induced injection pain, none of these has emphasized the affects of menstrual cycle on perception of pain.1,6 However, in a meta-analysis, Riley et al.2 emphasized that the effects of the menstrual cycle on the perception of pain were too distinct to ignore.
During the menstrual cycle, estradiol, progesterone and certain metabolites modulate neurotransmitter and neuropeptide activity in the central nervous system. Estrogens may influence mood and well-being in a favourable manner. Progesterone has an inhibitory effect on neuronal activities, which are mediated by excitatory and inhibitory amino acids and neuropeptides such as beta-endorphin.7 Although hormonal changes during the menstrual cycle have been well defined in humans, experimental and clinical studies examining the effects of the cycle on the perception of pain have yielded rather contradictory results.2 Some studies reported that the phases of menstrual cycle have no effect on pressure pain threshold and ishaemic pain tolerance.8–10 However, Stening et al.11 reported a decrease in pain threshold in cold pressure test during the late luteal phase and a significant correlation between increased pain sensitivity and increased progesterone concentration. Hellström and Anderberg12 have also demonstrated that pain was increased in the premenstrual phase with decreasing estrogen levels, which effect somatic sensory processes. Similarly, Bajaj et al.13 also reported that the change in pain threshold may be attributed to increased estrogen and luteinizing hormone during ovulation, effecting nociception peripherally and centrally. Elevated progesterone levels are reported to correlate with reduced ischaemic threshold and pressure tolerance, and this finding supports the role of progesterone during the early luteal phase.14 Also, the mood changes and the decrease in beta-endorphin levels in the late luteal phase may change the perception of pain.7,15 Previous studies have shown increased thermal pain threshold, thermal sense of cold threshold, pressure pain threshold and ischaemic pain threshold in the follicular phase than in other phases of the cycle.2,11–17 In our study, propofol pain was significantly lower in the follicular phase, known to have high estrogen levels, compared with the luteal phase in which high progesterone and low beta-endorphin levels are observed.
The limitation of our study is the absence of the measurements of estrogen and progesterone levels. However, similar to our study, several studies evaluating the effects of the menstrual cycle on postoperative nausea/vomiting5 and pain18 did not need to measure the hormone levels if the patients had regular menstrual cycles.
In conclusion, we suggest that menstrual cycle phases can affect the severity of propofol injection pain. Female patients may have lower propofol injection pain scores in the follicular phase of the menstrual cycle. Therefore, we suggest to learn the menstrual cycle phases of the female patients in the methodology of the studies investigating not only the injection pain of propofol but also different types of any pain.
1 Ayoğlu H, Altunkaya H, Ozer Y, et al
. Does dexmedetomidine reduce the injection pain
due to propofol
and rocuronium? Eur J Anaesthesiol 2007; 24:541–545.
2 Riley JL III, Robinson ME, Wise EA, Price DD. A meta-analytic review of pain
perception across the menstrual cycle
3 Erden V, Yangın Z, Erkalp K, et al
. Increased progesterone production during the luteal phase of menstruation may decrease anesthetic requirement. Anesth Analg 2005; 101:1007–1011.
4 Sener EB, Kocamanoglu S, Cetinkaya MB, et al
. Effects of menstrual cycle
on postoperative analgesic requirements, agitation, incidence of nausea and vomiting after gynecological laparoscopy. Gynecol Obstet Invest 2005; 59:49–53.
5 Gratz I, Allen E, Afshar M, et al
. The effects of the menstrual cycle
on the incidence of emesis and efficacy of ondansetron. Anesth Analg 1996; 83:565–569.
6 Sun NCH, Wong AYC, Irwin MG. A comparison of pain
on ıntravenous ınjection between two preparations of propofol
. Anesth Analg 2005; 101:675–678.
7 Kuhl H. Influence of the ovarian cycle on the central nervous system. Ther Umsch 2002; 59:175–181.
8 Vignolo V, Vedolin GM, de Araujo CR, Rodrigues CPC. Influence of the menstrual cycle
on the pressure pain
threshold of masticatory muscles in patients with masticatory myofascial pain
. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 105:308–315.
9 Okifuji A, Turk DC. Sex hormones and pain
in regularly menstruating women with fibromyalgia syndrome. J Pain
10 Kowalczyk WJ, Evans SM, Bisaga AM, et al
. Sex differences and hormonal influences on response to cold pressor pain
in humans. J Pain
11 Stening K, Eriksson O, Wahren L, et al
sensations to the cold pressor test in normally menstruating women: comparison with men and relation to menstrual phase and serum sex steroid levels. Am J Physiol Regul Integr Comp Physiol 2007; 293:R1711–R1716.
12 Hellström B, Anderberg UM. Pain
perception across the menstrual cycle
phases in women with chronic pain
. Percept Mot Skills 2003; 96:201–211.
13 Bajaj P, Arendt-Nielsen L, Bajaj P, Madsen H. Sensory changes during the ovulatory phase of the menstrual cycle
in healthy women. Eur J Pain
14 Viana ES, Bruno SS, de Sousa MB. Modulation by progesterone of pain
sensitivity to mechanical and ischemic stimuli in young and healthy women. Rev Bras Ginecol Obstet 2008; 30:306–311.
15 Viana ES, da Silva SB, de Sousa MB. Perception of ischemic and pressing pain
in young women during menstrual cycle
. Association with humor and cortisol levels. Acta Cir Bras 2005; 20:220–226.
16 Söderberg K, Sundström PI, Nyberg S, et al
. Psychophysically determined thresholds for thermal perception and pain
perception in healthy women across the menstrual cycle
. Clin J Pain
17 Isselée H, De Laat A, Bogaerts K, Lysens R. Long-term fluctuations of pressure pain
thresholds in healthy men, normally menstruating women and oral contraceptive users. Eur J Pain
18 Cimino R, Farella M, Michelotti A, et al
. Does the ovarian cycle influence the pressure-pain
threshold of the masticatory muscles in symptom-free women? J Orofac Pain
Keywords:© 2010 European Society of Anaesthesiology
injection; menstrual cycle; pain; propofol