1 Reproductive Medicine, Department of Obstetrics and Gynecology, Institute for the Health of Women and Children, Sahlgrenska University Hospital, Göteborg University, SE-413 45 Göteborg, 2 Institute of Occupational Therapy and Physiotherapy, Sahlgrenska Academy, Göteborg University, Box 455, SE-405 30 Göteborg and 3 Nordic School of Public Health, Box 12133, SE-402 42 Göteborg, Sweden
4 To whom correspondence should be addressed. Email: ann-louise.gejervall{at}vgregion.se
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Abstract |
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Key words: alfentanil/electro-acupuncture/IVF/oocyte aspiration/pain relief
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Introduction |
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Opiates are effective, but negative side effects such as tiredness, confusion and nausea may prolong the period to mobilization and recovery. A paracervical block (PCB), in combination with different sedative pre-medications with or without fast-acting opiates, has been reported to give acceptable pain relief during oocyte aspiration in several studies (Ng et al., 1999, 2001
). At our clinic, conventional analgesia during oocyte aspiration includes sedative pre-medication with oral flunitrazepam (Fluscand 0.5 mg; Pharmachemie BV, The Netherlands), rectal paracetamol (Panodil® 1 g; GlaxoSmithKline, Täby, Sweden), local analgesics (Xylocain® 10 mg/ml; Astra Zeneca, Södertälje, Sweden) administered as a PCB, and i.v. alfentanil (Rapifen® 0.5 mg/ml; Janssen-Cilag AB, Sollentuna, Sweden).
Acupuncture is a potent form of sensory stimulation, which has been introduced into Western medicine to treat different states of pain and disease (Stener-Victorin et al., 2002). Electrical stimulation of the needles, electro-acupuncture (EA), is a pain-relieving method that has been suggested to activate endogenous pain-inhibiting systems such as the spinal/segmental gate mechanism and the endogenous opioid system, including the descending pain inhibitory system (Andersson and Lundeberg, 1995
; Han, 2003
). It has been found to induce pain relief similar to that of fast-acting opiates during oocyte aspiration and to have fewer negative side effects (Stener-Victorin et al., 1999
, 2003
). EA has also been evaluated in different surgical procedures and reported to give acceptable pain relief during minor surgery and in post-operative pain (Fanti et al., 2003
).
Today, patients ask for non-pharmacological analgesic methods since they wish to avoid the negative side effects of opiates. EA may also be a good alternative for patients who are intolerant of conventional analgesia. Previous studies have investigated the analgesic effect of EA compared with opiates (Stener-Victorin et al., 1999, 2003
), but effects on the post-operative well-being of patients have not been evaluated in this context.
From a health economic perspective, it is also important to evaluate costs of new methods.
The primary aims of the present study were to investigate the pain-relieving effect of EA related to oocyte aspiration, and to evaluate post-operative well-being. Further aims were also to investigate time for post-operative mobilization, and costs for treatment concerning time and drug consumption.
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Methods |
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Study group
The study group consisted of women who were undergoing IVF and who consented to be randomized to the EA or the CA group for pain relief during oocyte aspiration. The women were informed about the study 2 weeks before oocyte aspiration. Inclusion criteria were willingness to participate in the study and knowledge of the Swedish language. Exclusion criteria were earlier participation in the study, epilepsy, a pacemaker, severe nickel allergy, or hepatitis B or C
A total of 621 women were eligible and 160 were randomized (Figure 1). The women were recruited between March 2002 and October 2003. Each woman enrolled by the physician or the midwife gave her written, informed consent before entering the study. Each woman underwent only one IVF cycle in the study.
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IVF treatment
All women underwent a stimulation procedure that included downregulation with a GnRH agonist begun either in the follicular phase or in the luteal phase (1.2 mg per day nasally or 1.0 mg per day as an s.c. injection; Suprecur or Suprefact; Hoechst, Frankfurt, Germany). Downregulation was followed by stimulation with recombinant FSH (Gonal-F, Serono, Geneva, Switzerland or Puregon, Organon, Oss, The Netherlands). Monitoring was performed via vaginal ultrasound scans and serum estradiol measurements. When adequate stimulation was achieved, 10 000 IU of HCG (Profasi, Serono or Pregnyl, Organon) was administered. Fertilization was performed by conventional IVF or by ICSI according to standard techniques. One or two embryos were transferred on day 2 or 3 after oocyte retrieval using a Wallace, a Cook or a Frydman catheter. Luteal support, progesterone, was administered vaginally. Additional embryos were cryopreserved and transferred later. Pregnancy was defined as a positive HCG test in urine on day 19 post-transfer.
Treatment procedure
EA was administered by four midwives who were educated and trained in the theoretical and practical knowledge of acupuncture and who all had long experience in the IVF unit. No pre-medication was given to the EA group. EA was administered 3045 min before oocyte aspiration and terminated directly after retrieval. Other midwives not involved in administering EA assisted in the analgesia procedure during oocyte retrieval. The intention was to follow the standard routines at the clinic and avoid any additional benefits of an emotional tie between the midwife and the patient in the EA group compared with the CA group. Acupuncture points and electrical stimulation were the same for all the women in the EA group. The acupuncture points selected were located bilaterally in the abdominal muscles in somatic segments related to the pain area for the uterus and the ovaries (KI 11 and ST 29). Additional points at sites in the muscles below the knee and elbow were selected bilaterally in the arm (LI 10), the hand (LI 4), and just below the knee (ST 36) to extend and prolong the effect of EA stimulation. The point GV 20, on the top of the cranium, was chosen to increase relaxation based on an empirical recommendation in traditional Chinese medicine. The stainless steel needles (Hegu Xeno: Hegu AB, Landsbro, Sweden; size 0.30 x 30 or 50 mm) were inserted intramuscularly to a depth of 1530 mm. Points ST 36 and GV 20 were stimulated manually every 10th minute by hand to evoke needle sensations and increase activity in the afferent nerves and central pain systems. The points LI 4, LI 10, ST 29 and KI 11 were stimulated electrically. These needles were attached to an electrical stimulator (CEFAR ACUS 4, Cefar, Lund, Sweden) and were electrically stimulated with square-wave pulses (0.18 ms duration) with alternating polarity. The stimulation frequency in the abdomen was high, 80 Hz, while the frequency used in the hands was low, 2 Hz, with burst pulses (a burst length of 0.1 s and a burst frequency of 80 Hz). The high-frequency stimulation intensity induced strong but non-painful paraesthesia with the aim of influencing the spinal cord and activating the gate control system (Stener-Victorin et al., 1999, 2003
). The low-frequency stimulation induced non-painful local muscle contractions with the aim of releasing
-endorphins centrally and reducing the sensation of pain.
The CA group received a sedative pre-medication consisting of 0.5 mg of oral flunitrazepam and 1 g of rectal paracetamol prior to the PCB. In the operating theatre, 0.5 mg of alfentanil was administered i.v. before oocyte retrieval was begun.
A PCB consisting of lidocaine (0.5%) was administered to both groups just before oocyte aspiration.
If EA or CA did not result in sufficient pain relief, additional alfentanil or nitrox (AGA, Stenungsund, Sweden) was administered.
A heat therapy pillow was used on the abdomen before, during and after surgery in both groups to increase relaxation and decrease pain (Uvnäs-Moberg et al., 1993).
In accordance with post-operative mobilization procedures, patients were observed for wakefulness and offered breakfast every 30 min.
Time consumption and costs
Costs for time and drug consumptions in the study were recorded and compared between the EA group and the CA group (Table VI). Costs for time consumption comprised patients' total time at the clinic in minutes, counted in terms of the midwives' salary. The comparison of drug costs between groups was based on total drug consumption, which included pre-medication, peroperative consumption of opiates and post-operative intake of analgesics. Costs for acupuncture and costs for aspiration needles were counted separately.
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Visual Analogue Scale
To evaluate subjective pain and subjective experiences, the VAS was used for measurements. The VAS questionnaire contained 29 different variables (Babul et al., 1993; Altman, 1996
; DeLoach et al., 1998
), each consisting of a 100 mm horizontal line with suitable end-points. The questionnaire was administered on four occasions (Table III): (i) before randomization; (ii) directly after oocyte aspiration; (iii) 60 min after surgery; and (iv) when the patient had recovered. The VAS questions asked on the four occasions had the end-points shown in Table I.
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Sample size calculation
A sample size calculation was made prior to the study based on the following assumption for the primary end-points: if STAI measurements of well-being 60 min after oocyte aspiration had an expected SD of 10.0 in each group, 68 patients would be needed in each group to show a significant difference between groups of 5.0 with a power of 80% and a significance level of 0.05.
To demonstrate equal levels of pain between the groups, directly related to oocyte aspiration and measured with a VAS, the following assumptions were made: given an SD of 18.0 in each group concerning pain assessed by VAS directly after oocyte aspiration, 80 patients in each group would be needed to show that the upper limit of the 95% confidence inteval (CI) for the difference in means between the groups should not exceed 11.0 with a probability of 0.80.
Statistics
The statistical analysis was made primarily according to intention to treat, i.e. a strict analysis according to randomization group regardless of subsequent protocol violation. In the secondary per protocol analysis, patients were allocated to treatment groups according to the actual treatment given (EA or CA). The primary outcomes were well-being 60 min after surgery and pain related to oocyte aspiration. The secondary outcomes were tiredness and confusion. For descriptive statistics, mean, SD, median and range were used.
Subgroup analyses were performed for three different groups consisting of first cycle patients, patients who were anxious prior to oocyte aspiration and patients who were calm prior to oocyte aspiration. Patients were defined as calm at VAS levels of 22 mm or anxious at VAS levels >22 mm prior to oocyte aspiration.
Since the number of collected oocytes differed significantly between the groups and might have influenced pain, P-values were adjusted for the number of oocytes. Adjustments were made by logistic regression analysis.
Spearman's rank correlation test was used to describe the correlation between two continuous variables; the MannWhitney U-test was used for comparisons between continuous variables; Fisher's exact test was used for comparisons between dichotomous variables.
A multivariate analysis with stepwise linear regressions was made on the outcomes; pain and tiredness as the dependent variables. The dependent factors were transformed with Blom's rank method to achieve a normal distribution of variables (Blom, 1958). Independent variables tested were age, number of aspiration, analgesic group, number of oocytes, STAI form Y-1 and form Y-2, VAS I anxiety prior to oocyte aspiration, and fear of pain.
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Results |
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VAS after oocyte aspiration
The assessment of momentary pain after retrieval showed that pain was significantly less in the CA group compared with the EA group. The pain related to oocyte aspiration was also significantly less in the CA group. The CA group was significantly more tired and confused directly after retrieval compared with the EA group.
VAS 60 min after oocyte aspiration
Sixty minutes after oocyte aspiration, no significant differences in pain ratings between the two groups were noted. The CA group was still significantly more confused 60 min after oocyte aspiration compared with the EA group.
VAS at recovery
At recovery, the EA group rated oocyte aspiration as significantly more painful than expected. At the same time point, women in the CA group reported that they were significantly more satisfied with oocyte aspiration compared with the EA group. At recovery, no significant differences in tiredness and confusion between the groups were found.
Adjustments for the number of oocytes did not alter the results for any of the pain assessments.
The results from the three subgroup analyses, including first cycle patients, anxious patients prior to oocyte aspiration, and calm patients prior to oocyte aspiration, were similar to those for the total study group (data not shown).
The analgesic groups and STAI form Y-1 were found in the regression analyses (Tables IV and V) to be independently correlated with pain during oocyte aspiration. Age, number of oocytes and analgesic groups were independently correlated with tiredness.
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Well-being
No significant differences in well-being between the two groups as measured with the STAI were noted at any occasion (Table VIII).
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Discussion |
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In the present study, 25 women in the CA group refrained from pre-medication. Therefore, an analysis to compare reported pain levels between the women who used pre-medication and those who did not in the CA group was made. No difference in reported pain was found (P=0.483). In comparisons with the EA group, the two pre-medication subgroups still reported significantly lower levels of pain.
One factor that might influence pain ratings is that the questions related to pain in the present study were not the same as those used in earlier studies, which might make comparisons between studies difficult (Stener-Victorin et al., 1999, 2003
; Humaidan and Stener-Victorin, 2004
).
Another possible explanation for the significantly higher pain reported by the EA group in the present study might be that the study group was less homogenous. Since results from previous studies found similar pain-relieving effects between EA and opiates, it might have been easier in the present study for the medical staff to recruit women whose attitudes towards non-pharmacological methods varied more and was less positive than in previous studies.
An interesting observation was that the women randomized to EA sometimes resisted additional alfentanil despite insufficient pain relief from EA. When asked about it afterwards, the women could not give an explanation. Many women emphasized that they had invaluable support in coping with the pain from the medical team. Patient motivation and support from the medical team seem to be very important components of pain relief.
It is known that the pain-relieving effect of EA can be lowered if patients feel emotionally unsafe and uncomfortable with the method (Harro et al.; 1993; Widerström-Noga et al., 1998
; Cohen et al., 1999
).
The EA group reported significantly lower levels of tiredness and confusion after oocyte aspiration and were significantly less confused during the first 60 min after oocyte retrieval. These findings were expected. The women in the EA group expressed satisfaction with less tiredness and confusion compared with the CA group.
No significant differences in time for mobilization or in total costs between the EA and the CA groups were noted. Humaidan and Stener-Victorin (2004) reported that hospitalization time was significantly shorter and costs were significantly lower in the EA group.
In the present study, the EA group used significantly less additional alfentanil during surgery compared with the CA group. The use of less additional alfentanil is in line with the findings of previous studies (Stener-Victorin et al., 2003; Humaidan and Stener-Victorin, 2004
). A reduction in the use of opiate medication during oocyte aspiration may be desirable, as alfentanil is found in the follicular fluid shortly after i.v. administration (Soussis et al., 1995
). Furthermore, recent studies evaluating the analgesic effect of EA during colonoscopy have confirmed that EA analgesia decreases the consumption of additional drugs during and after surgery (Wang et al., 1997
). It has also been confirmed that when additional drugs are administered in combination with EA, lower doses of opiates provide sufficient pain relief (Wang et al., 1997
; Fanti et al., 2003
).
No differences in any clinical IVF outcome parameters between the two groups were found. No negative side effects were reported, which is in line with the results of previous studies made under similar conditions (Wang et al. 1997, Fanti et al. 2003
).
In conclusion, EA cannot generally be recommended as a pain-relieving method at oocyte retrieval but might still be an analgesic alternative for women who wish to try a non-pharmacological method. Women in the EA group were less tired and confused after oocyte aspiration, and 50% of the women in the EA group reported that they were willing to use EA again as an analgesic method. Since pain varies from individual to individual, it is important to individualize the analgesic procedure.
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Acknowledgements |
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References |
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Submitted on September 15, 2004; resubmitted on November 11, 2004; accepted on November 22, 2004.
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