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CLINICAL INVESTIGATION
Year : 2007  |  Volume : 51  |  Issue : 6  |  Page : 519-524 Table of Contents     

Correlation of serum oestrogen level with duration of post operative analgesia


1 Sr. Prof. & Head, Department of Anaesthesiology and M. P. Shah Medical College, Jamnagar - 361008, India
2 P.G. Student, Department of Anaesthesiology and M. P. Shah Medical College, Jamnagar - 361008, India
3 Assistant Professor, Department of Anaesthesiology and M. P. Shah Medical College, Jamnagar - 361008, India
4 Former Dean, Department of Anaesthesiology and M. P. Shah Medical College, Jamnagar - 361008, India

Date of Acceptance15-Sep-2007
Date of Web Publication20-Mar-2010

Correspondence Address:
Pramod Kumar
Professor and Head, Department ofAnaesthesiology, M.P.Shah Medical College and Guru Gobind Singh Hospital, Jamnagar
India
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Source of Support: None, Conflict of Interest: None


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Sixty female patients ofASAstatus I and II posted for routine surgical procedures like abdominal hysterectomy, exploratory laparotomy, pyelolithotomy, laparoscopic cholecystectomy etc. were studied for correlation of serum oestrogen level and post operative analgesia. The patients were divided into 3 groups, each consisting of 20 patients. Group-I consisted of female patients in Ist phase of menstrual cycle, Group-II of female patients in II nd phase of menstrual cycle& Group-III of female patients in IIIrd phase of menstrual cycle.All patients were premedicated with glycopyrrolate 4μg.kg -1 and midazolam 0.02 mg.kg -1 intravenously just before induction. All patients were given general anaesthesia with sodium thiopentone 5 mg.kg -1 and succinylcholine 1.5 mg.kg -1 and maintained with O 2 + N 2 O=30:70, fentanyl 1 μg.kg -1 pancuronium 0.08mg.kg -1 bolus and .02 mg.kg -1 given in intermit­tent doses. Patients were reversed with neostigmine 50 μg.kg -1 and glycopyrrolate 8 μg.kg -1 given intravenously slowly. All patients were monitored for pulse, BP, SpO2, RR, tidal volume and minute volume. After recovery of patient, when patient complained of pain, buprenorphine 4μg.kg -1 was given intravenously. Additional supplements of diclofenac sodium were given if needed after the effect of buprenorphine was over upto 24 h. Before induction of anaesthesia, 5ml of patient's venous blood was collected to measure serum oestrogen level by ELISA method and analgesia after buprenorphine was assessed by VAS score.
The results analysed showed that there was a clinically significant but statistically non significant reduction in 24hr VAS score in Group I& III patients than Group II patients who had a high oestrogen level. A negative correlation between serum oestrogen and mean duration of analgesia further support this, indicating that low serum oestrogen level decreases pain sensitiv­ity and high serum oestrogen level increases pain sensitivity.

Keywords: Serum oestrogen; Postoperative pain; Gender; Menstrual cycle


How to cite this article:
Kumar P, Jaspreet K, Pujara J, Anand J S. Correlation of serum oestrogen level with duration of post operative analgesia. Indian J Anaesth 2007;51:519-24

How to cite this URL:
Kumar P, Jaspreet K, Pujara J, Anand J S. Correlation of serum oestrogen level with duration of post operative analgesia. Indian J Anaesth [serial online] 2007 [cited 2020 Aug 5];51:519-24. Available from: http://www.ijaweb.org/text.asp?2007/51/6/519/61191


   Introduction Top


Many factors affect pain viz. - patient's age, weight, gender [1] , psychological status of patients, culture & site and extent of surgery [2] .

A number of animal and human studies have been reported suggesting the role of gonadal hormones such as oestrogen [3] , progesterone [4] and testosterone [5] in modu­lating the nociceptive transmission.

The present study was conducted with respect to the hormone oestrogen which regulates nociception via intracellular ERa and ERb receptors which in turn con­trol gene transcription, alter second messenger pathways and neuronal excitability [6] .

Because of the interplay of factors such as vari­ous other steroidal hormones, psychosocial factors etc., there is a conflicting opinion between various authors regarding pro / anti nociceptive role of oestrogen [3],[7] .

Moreover, the lack of definitive human studies with regards to the effect of steroidal hormones on post op­erative pain as well as the non inclusion of important parameters such as VAS score and haemodynamic data in the available studies prompted the present study cor­relating serum oestrogen level with postoperative pain relief using intravenous buprenorphine in female patients.


   Methods Top


Sixty female patients ofASAstatus I and II posted for routine surgical procedures lasting 1-2 h in age group of 25-45 years and body weight 40-60 kg were studied for correlation of serum oestrogen level and postopera­tive analgesia. The patients were divided into 3 groups.

Group -I Female patients in Ist phase (1 - 10 days) of menstrual cycle (n=20)

Group -II Female patients in IInd phase (11 - 20 days)of menstrual cycle (n=20)

Group -III Female patients in IIIrd phase (21 - 30 days) of menstrual cycle (n=20)

A detailed history and thorough physical examina­tion was undertaken so as to exclude patients with his­tory of undue anxiety, females at menopause, very young or old patients. The patient's vital signs in the form of pulse rate, blood pressure, respiratory rate, tidal volume and minute volume by Wright's respirometer and oxy­gen saturation by pulse oximeter were monitored preop­eratively. The patients were also monitored for side ef­fects e.g. nausea, vomiting, respiratory depression, se­dation and retention of urine.

Just before induction, all patients were premedi­cated with glycopyrrolate 4µg.kg -1 and midazolam 0.02 mg.kg -1 intravenously slowly. Five ml of venous blood was collected just before induction and serum oestrogen level was measured by ELISA method. All patients re­ceived general anaesthesia comprising of thiopentone sodium 5 mg.kg -1 and succinylcholine 1.5 mg.kg -1 and orotracheal intubation was done with appropriate endot­racheal tube and maintained with O 2 : N 2 O = 30:70, fen­tanyl 1 µg.kg -1 and pancuronium with bolus 0.08 mg.kg­1 and 0.02 mg.kg -1 IV intermittently. The patients were reversed with neostigmine 50 µg.kg -1 and glycopyrrolate 8 µg.kg -1 IV slowly. Pulse rate and mean arterial pres­sure were recorded before induction, after induction, 30 min, 1h and 2h interval during surgery.

After completion of procedure, patients were shifted to recovery unit and when the patients complained of pain, buprenorphine 4 µg.kg -1 IV was given in pa­tients with VAS score more than 3. The patients received diclofenac sodium 1.5 mg.kg- 1 intravenously afterwards as additional analgesic supplement if required.

Analgesia was measured by VAS score at zero, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h interval after buprenorphine injection respectively. PR & MAP were also recorded at these time intervals. The correlation coefficient was measured between serum oestrogen and duration of analgesia, using following formula.



In this formula

n=total no. of patients in particular group.

X=Serum oestrogen level (pg.ml -1 ).

Y=duration of analgesia (h).

This formula is applicable when number of patients in particular group are 20 or more than 20.

Significance of this formula is that it is used to find out relation between two parameters. If value comes between-1 to 0, it shows that two parameters are in­versely related to each other, if value comes between 0 to +1, it shows that two parameters are directly re­lated to each other. If values comes zero, that means no relation between two parameters.


   Results Top


There was no statistically significant difference between age, weight, height [Table 1],ASAstatus, types of surgery and duration of surgery in all 3 groups. There was no significant change (P>0.05) in mean pulse rate and mean arterial pressure (MAP) from the preinduc­tion value in all groups during intraoperative period while there was a statistically significant rise in pulse rate in Group II and III and MAP in Group II at 8 h interval due to pain while values were not significant at other postop­erative intervals [Table 2]. The patients were given buprenorphine 4 µg.kg -1 IV postoperatively when they complained of pain (VAS > 3), thereafter duration of analgesia was recorded. The serum oestrogen levels in Group I, II and III plotted against the days of menstrual cycle [Figure 1], showed low serum oestrogen level in the first phase of menstrual cycle (1-10 days) which in­creased in the second phase (11-20 days). In the last phase (21-30 days) the level of serum oestrogen again decreased. Duration of analgesia in various phases of menstrual cycle is shown in [Figure 2].

In Group I, mean duration of buprenorphine anal­gesia was 14.28 (± 8.96 SD) h and mean serum oestro­gen level was 58.93 (± 45.89 SD) pg.ml. -1 In Group II, duration of buprenorphine analgesia was 8.50 (±6.92 SD) h and mean serum oestrogen level was 185.31 (±49.68, SD) pg.ml -1 , while in Group III, duration of buprenorphine analgesia was 11.90 (±7.82 SD) h and mean serum oestrogen level 101.96 (±47.05 SD) pg.ml -1 . The addi-tional analgesic supplements of 24 h post operative diclofenac sodium received after the buprenorphine ac­tion was over, shows highest dose needed in Group II (2.60 ± 11.33) mg.kg -1 followed by Group III (2.35 ± 10.24) mg.kg -1 and least in Group I (1.65± 10.24) mg.kg­1 [Table 3]. The mean value of 24 hour VAS score was minimum in Group I (3±4.76) and Group III (3.5±3.15) females and maximum in group II females (4±4.87), re­flecting less pain in Group I & III as compared to ovula­tory Group II. However, when inter group comparison was done, this difference was statistically non signifi­cant [Table 4].

The correlation coefficient between duration of analgesia following buprenorphine and serum oestrogen level was negative in all 3 groups, which means that, when level of serum oestrogen was maximum, duration of analgesia was minimum and vice versa. This correla­tion has been plotted graphically in graph 3 (A, B, C) showing negative correlation between duration of buprenorphine analgesia and serum oestrogen level.

There was no associated clinically significant com­plication eg. nausea, vomiting, respiratory depression and retention of urine in any of the patients of this study.

The correlation coefficient between duration of analgesia following buprenorphine and serum oestrogen level was negative in all 3 groups, which means that, when level of serum oestrogen was maximum, duration of analgesia was minimum and vice versa. This correla­tion has been plotted graphically in graph 3 (A, B, C) showing negative correlation between duration of buprenorphine analgesia and serum oestrogen level.

There was no associated clinically significant com­plication eg. nausea, vomiting, respiratory depression and retention of urine in any of the patients of this study.


   Discussion Top


Since long steroidal hormones have been implicated in modulation of different types of nociceptive stimuli like neuropathic pain, chronic pain, regional pain syn­dromes and acute pain including postoperative pain. [2] . Examples of these steroidal hormones are oestrogen, [3] progesterone [4] and testosterone [5] . Of these hormones oestrogen has been vastly studied in relation to its modu­lation of nociception mechanisms.

There are a few contradictions between different authors regarding the role of oestrogen as a pro or an anti nociceptive agent. [3],[7] The present study is an effort to clear some of the concepts with regards to the role of oestrogen in postoperative pain.

Some of the possible mechanisms by which oestrogen may affect the nociceptive transmission are as follows:

  • The normal level of serum oestrogen varies in dif­ferent phases of menstrual cycle in female [7].
  • Steroids modulate neuronal excitability through in­teraction with neurotransmitter receptors including NMDA, non NMDA, GABA and opioid receptors [8].
  • Oestrogen may modulate descending inhibition on spinal dorsal horn neurons from supraspnal sites or alter inhibitory processing in spinal cord [9].
  • Oestrogen also reportedly decreased the binding of NMDA and AMPA receptors in certain brain areas such as frontal cortex and the nucleus accumbens which are involved in modulation of pain percep­tion [10].
  • Short term treatment with oestrogen in ovariecto­mized rats also decreased the number of opioid bind­ing sites in the brain, thus decreasing the analgesic effects of morphine [11].
  • Due to oestrogen and opioid interactions in dorsal horn, different response is seen towards Kappa - agonists buprenorphine, butorphanol [12] and U 50 [13].


Mean duration of analgesiawas minimumin females during the IInd phase of menstrual cycle (Group II) in which serum oestrogen level was maximum.Additionally VAS score was maximum in females having maximum serumoestrogen level (Group II). Haemodynamic changes also showed that analgesia was maximumin patients with lower serum oestrogen levels.

The findings of present study are supported by the studies of following authors:

Zhao X et al [14] who stated that oestrogen by el­evating the level of BDNF (Brain Derived Nerve Fac­tor) potentiates the sensitivity to thermal stimuli.

In another study [15] comparing the magnitude of vis­ceromotor reflex (VMR) in intact cycling female rats and ovariectomized rats in response to colorectal disten­tion (CRD) it was suggested that there was significant reduction of magnitude of VMR in ovariectomized rats and when these rats were administered oestrogen (10 mg - 50 mg), there was significant facilitation of VMR.

In a study involving male rats [16] it was concluded that controlled administration of oestradiol increased the amount of licking of formalin injected paw and adminis­tration of ER oestrogen receptors antagonist reversed this phenomenon.

The oestrogen rapidly modulates behavioural re­sponsiveness to painful stimulus at spinal cord level proven by the fact that spinal aromatase inhibition leads to rapid increase in foot withdrawal latency from a 54°C water bath [17] .

However some of the authors observed contra­dicting results.

In a study on female rats it was suggested that long term ovariectomy resulting in lower oestradiol and corticosterone, prolonged formalin induced licking and also altered thermal pain threshold [18] . This implies that long term depletion of gonadal hormones modulates pain induced behavioural responses related to supraspinal neural circuits.

In a study on human volunteers (20 women with chronic low pain) it was suggested that pain was rated significantly high during menstrual and premenstrual phases than in midmenstrual and ovulatory phases [19] . This implies that high serum oestrogen due to its effect on somatic sensory process causes less pain sensitivity.

In another study on male and female rats it was suggested that oestrogen and testosterone both reduce the pronociceptive actions of isoflurane, which was proved by the fact that both castrated and oophrectomy resulted in an increase in baseline pain sensitivity.They also stated that testosterone is effective because of its conversion to oestrogen [3] .

In a study involving mice it was suggested that two types oestrogen receptors (ER), ERa and ER(3 are found in rat dorsal root ganglion (DRG) neurons.In DRG neurons from ERa knockout mice 17(3 oestra­diol failed to inhibit the ATP induced [Ca 2+ ] increase, which implies that oestradiol induced attenuation ofATP induced [Ca 2+ ] signalling is mediated by membrane as­sociated ERα receptor [20] .

Even after careful search, no other study could be found which dealt directly with the effect of oestrogen on postoperative pain and in no available human studies was a comment made on VAS score and haemodynamic parameters.Although studies to indirectly correlate psy­chophysiological response to stress has been attributed to sex hormones. [21]

The present study showed a negative correlation between the duration of buprenorphine analgesia and serum oestrogen level. Further the higher mean VAS and mean dose of additional analgesic supplements needed during 24 h period in high oestrogen level group also corroborates this inverse relationship.

To conclude this discussion, it is felt that there is a need for a larger, more specific controlled trial with regards to female sex at different phases of menstrual cycle as well as during pregnancy and menopause. And also studies with reference to the effects of other hor­mones such as progesterone and testosterone acting in conjunction with oestrogen in modulation of nocicep­tive transmission are needed. Thus a combined role of these hormones and other psychosocial factors may explain the various contradictory findings obtained by different authors.[Figure 3]

 
   References Top

1.Parbrook G D and Steel D F. Factors predisposing to postop­erative pain. A study of male patients undergoing elective gas­tric surgery. Br J Anaesth 1973; 45 : 21.  Back to cited text no. 1      
2.Kumar P. A text book of pain. Ist Eds., Modern Publishers, 2006, 35-43.  Back to cited text no. 2      
3.Flood P and Daniel D. Pronociceptive actions of isoflurane : a protective role of estrogen. Anesthesiology 2003; 99 : 476-90.  Back to cited text no. 3      
4.Gintzler AR, Bohan MC. Pain thresholds are elevated during pseudopregnancy. Brain Res 1990; 507 : 312-316.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Gooren LJ and TooriansAW. Significance of oestrogens in Male (Patho.) Physiology. Ann. Endocrinol (Paris) 2003; 64 : 126­35.  Back to cited text no. 5      
6.Joels M. Steroid hormones and excitability in the mammalian brain. Front Neuroendocrinol 1997; 18 : 2-48.  Back to cited text no. 6      
7.R Rajan. Biology and Pharmacology of oestrogens. In post­graduate reproductive endocrinology. 4th edition. Jaypee Broth­ers, New Delhi, 1997, 38.  Back to cited text no. 7      
8.Majewska MD. Neurosteroids; endogenous bimodal modula­tors of the GABA receptor. Mechanism of action and physi­ological significance. Prog Neurobiol 1992; 38 : 379-395.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Amandusson A, Hermanson O, Blomqvist A. Colocalization of oestrogen receptor immunoreactivity and preproenkephalin mRNA expression to neurons in the superficial laminae of the spinal and medullary dorsal horn of rats. Eur J Neurosci 1996; 8 : 2440-2445.  Back to cited text no. 9  [PUBMED]    
10.Bushnell MC, Duncan GH, Hofbauer RK, et al. Pain percep­tion : is there a role for primary somatosensory cortex ? Proc Natl Acad Sci USA 1999; 96 : 7705-7709.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Berglund LA, Derendorf H, Simpkins JW. Desensitization of brain opiate receptor mechanisms by gonadal steroid treat­ments that stimulate luteinizing hormone secretion. Endocri­nology 1988; 122 : 2718-2726.  Back to cited text no. 11      
12.Amandusson A, Hermanson O, Blomqvist A. Estrogen recep­tor like immunoreactivity in the medullary and spinal dorsal horn of the female rat. Neurosci Lett 1995; 196 : 25-28.  Back to cited text no. 12  [PUBMED]    
13.Sternberg WF, Ritchie J, Mogil JS. Qualitative sex differences in Kappa - opioid analgesia in mice are dependent on age. Neurosci Lett 2004; 363 : 178-81.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Zhoa X, Liu J, Guan R, et al. Estrogen affects BDNF expres­sion following chronic constriction nerve injury. Neuroreport 2003; 14 : 1627-1631.  Back to cited text no. 14      
15.Yaping Ji, Anne Z Murphy and Richard J. Traub. Estrogen modulates the visceromotor reflex and responses of spinal dor­sal horn neurons to colorectal stimulation in the rat. Journ Neuroscience 2003; 23: 3908.  Back to cited text no. 15      
16.Ceccarelli I, Fiorenzani P. Massafra C, et al. Long term ovariec­tomy changes formalin induced licking in female rats : the role of estrogens. Reprod Biol Endocrinol 2003; 14; 1-24.  Back to cited text no. 16      
17.Henry C Evrard and Jacques Balthazart. Rapid regulation of pain by estrogens synthesized in spinal dorsal horn neurons. Journ Neurosci 2004; 24 : 7225-90.  Back to cited text no. 17      
18.Ceccarelli I, Fiorenzani P, Grasso G, et al. Estrogen and mu­opioid receptor antagonists counteract the 17 beta estradiol induced licking increase and interferon gamma reduction occur­ring during the formalin test in male rats. Neuroreport 2003; 14 : 1627-31.  Back to cited text no. 18      
19.Hellstrom B and Anderberg UM. Pain perception across the menstrual cycle phases in women with chronic pain. Percept Mot Skills 2003, 96 : 201-11.  Back to cited text no. 19      
20.Chaban VV, Micevych PE. Estrogen receptor alpha mediates estradiol attentuation ofATP induced [Ca 2+ ] i signaling in mouse dorsal root ganglion neurons. J Neurosci Res 2005; 81 : 31-7.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]  
21.Kajantie E, Phillips DI. The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinolgy 2006; 31, 151-78.  Back to cited text no. 21      


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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