Pain relief during oocyte retrieval with a new short duration electro-acupuncture technique—an alternative to conventional analgesic methods

Peter Humaidan1 and Elisabet Stener-Victorin2,3

1 The Fertility Clinic, Skive Sygehus, DK 7800 Skive, Denmark and 2 Department of Obstetrics and Gynecology and Department of Physiology and Institute of Occupational Therapy and Physiotherapy, Sahlgrenska Academy, Göteborg University, Box 455, SE 405 30 Göteborg, Sweden

3 To whom correspondence should be addressed. e-mail: elsv{at}fhs.gu.se


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Acupuncture previously has proved its pain-relieving effect for ovum pick-up (OPU). The analgesic effect of electro-acupuncture (EA) was evaluated when EA was applied for only a few minutes prior to OPU in an attempt to make EA more attractive for clinical use. METHODS: Two hundred patients undergoing OPU were randomized prospectively using sealed, unlabelled envelopes, to receive pain relief with either EA in combination with a paracervical block (PCB) (n = 100) or conventional medical analgesia (CMA) in combination with a PCB (n = 100). A visual analogue scale (VAS) was used to evaluate pain and anxiety before, during and after OPU. The primary outcome measure was pain relief; secondary end-points were costs, time to discharge and clinical outcome parameters. RESULTS: There were no differences in any VAS ratings before the procedure. Directly after OPU, the EA group reported significantly higher mean and maximum pain, and ‘pain now’ than the CMA group. At 30 min after OPU and thereafter, no significant differences were found between the groups regarding abdominal pain. Time to discharge and costs were significantly lower in the EA group compared with the CMA group. No differences in clinical outcome parameters were seen. CONCLUSION: A significant difference was found between the EA and the CMA groups regarding pain during the OPU, probably due to the fact that the CMA group was pre-medicated as part of the study design. Despite a per-operative difference in pain rating, EA, given a few minutes prior to OPU, is a good alternative to CMA. The procedure is well tolerated by the patients, with a shorter hospitalization time and lower costs.

Key words: analgesia/electro-acupuncture/IVF/ovum pick-up/pain relief


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Conscious sedation appears to be the most commonly used analgesic method for ovum pick- up (OPU) (Trout et al., 1998Go). In many clinics, conventional medical analgesia (CMA) during OPU includes sedative pre-medication with benzodiazepine, local analgesics administered as a paracervical block (PCB) and i.v. fast-acting opiates administered during OPU. CMA involves a number of side effects such as nausea, tiredness and confusion. Agents such as alfentanil and lidocaine have been detected in the follicular fluid during OPU shortly after injection (Wikland et al., 1990Go; Soussis et al., 1995Go). The possible negative consequences of these agents in human follicular fluid have not been clearly demonstrated.

Acupuncture, a method of treatment that dates back at least 3000 years, has proved its pain-relieving effect both intra-operatively and post-operatively (Kho et al., 1991Go; Wang et al., 1997Go; Fanti et al., 2003Go). Acupuncture with needle penetration of the skin and underlying muscles, followed by stimulation of the needles by manual rotation or by electrical stimulation—so called electro-acupuncture (EA)—excites afferent nerve fibres. When the needle is located and stimulated in the same segment as the pain, information from the excited fibres is known to inhibit pain transmission at the spinal level, and to activate the central endogenous opioid system including the descending pain inhibitory systems. At the same time, psychological responses are generated (Lundeberg and Stener-Victorin, 2002Go). The advantage of acupuncture is its very few negative side effects.

In two recent studies, the analgesic effect of EA in combination with a PCB was compared with alfentanil (a fast-acting opiate) in combination with a PCB during OPU. In these trials, no pre-medication was used in either group and EA was applied 30 min before OPU. EA and a PCB was reported to be as effective as alfentanil and a PCB, without any reported negative side effects (Stener-Victorin et al., 1999Go, 2003). There were no differences between the groups regarding mean and maximal pain experienced during OPU. Two hours after OPU, women who received EA as analgesia during OPU reported significantly less abdominal pain, nausea and stress compared to women who received alfentanil as analgesia (Stener-Victorin et al., 2003Go). In addition, the EA group received significantly less additional opiates (Stener-Victorin et al., 2003Go). Another interesting observation in the first trial (Stener-Victorin et al., 1999Go) was a significantly higher pregnancy rate in women who received EA as analgesia. In the second trial, however, when a larger number of patients were included, EA did not improve the pregnancy rate when used as an analgesic method during OPU (Stener-Victorin et al., 2003Go). As mentioned, EA stimulation was applied at least 30 min before OPU in both trials. This was due to the results of a previous study on acupuncture and pain relief in which 30 min was considered to be the optimal time needed for a thorough onset of analgesia and relaxation prior to operation (Bonica, 1974Go). When EA is applied 30 min prior to OPU, the patient has to move to the operating theatre with the acupuncture needles in situ, which is inconvenient and might dislocate needles. In order to make EA more attractive for clinical use, it would be of interest to investigate whether EA, when applied a few minutes before OPU and terminated directly after OPU, induces sufficient pain relief and analgesia during OPU. The primary end-point of the study was pain relief. Secondary end-points were costs, time to discharge and clinical outcome parameters. An EA treatment protocol commonly used for gynaecological pain relief in Denmark was employed.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Setting, study design, participants and randomization
The prospective randomized study was performed between April 2002 and December 2002 at the Fertility Clinic, Skive Hospital, Denmark. The CONSORT guidelines for reporting of randomized trials were followed (Moher et al., 2001Go). All patients included in our IVF programme were informed about the study ~3 days to 1 week before the OPU. No exclusion criteria were used. Each patient gave her written informed consent before participating in the study and contributed data from one cycle only. Randomization was performed by a nurse on the day of the last ultrasound examination before OPU, using sealed, unlabelled envelopes, each containing a unique study number. A total of 200 patients were recruited and randomly allocated to the EA or the CMA groups (Figure 1). The patients allocated to the EA group were randomized to receive EA in combination with a PCB during OPU. The patients allocated to the CMA group were randomized to receive CMA in combination with a PCB during OPU. The participants were told that they could discontinue the study at any time. The local Ethics Committee of Viborg County, Denmark approved this prospective, randomized study.



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Figure 1. Patient flow through different stages of the RCT.

 
Analgesic protocol
PCB. Both study groups received a PCB of 10 ml of lidocaine (5 mg/ml lidocaine hydrochloride; Lidocain®, SAD, Amternes lægemiddelregistreringskontor I/S, Denmark). Lidocaine was injected where the aspiration needle was intended to pass through the vaginal wall.

EA. In the EA group, the acupuncture needles (HUANQIU, AcupunctureShop, Varde, Denmark; size 0.30 x 30 mm) were inserted 15–25 mm intramusculary into the acupuncture points (Table I) a few minutes before the OPU. The selected acupuncture points are commonly used for gynaecological pain relief in Denmark. The needles in the abdominal muscles and in the hands were connected to an electrical stimulator (Agistim Duo®) and stimulated with a frequency of 20 Hz at a continuous pulse duration of 0.5 ms. The stimulation intensity was as high as possible, just under pain threshold. The stimulation intensity of the needles was adjusted continuously during the procedure. Well-trained nurses administered the acupuncture. The PCB was given ~1–2 min after the EA procedure started. At the end of the procedure, the acupuncture needles were removed.


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Table I. Acupuncture points (anatomical position and innervation) used together with a PCB during the ovum pick-up procedure
 
No pre-medication was administered to the EA group. If sufficient pain relief was not obtained by EA alone, patients were supplemented with i.v. alfentanil (0.25 mg) (Rapifen; Janssen-Cilag A/S, Birkeröd, Denmark).

CMA. In the CMA group, patients were pre-medicated with benzodiazepine 10 mg p.o. (Stesolid; Dumex-Alpharma A/S, Copenhagen, Denmark) 1 h before the OPU. Immediately before the application of the PCB, 0.25 mg of alfentanil was given i.v. The alfentanil bolus was repeated 1–3 times during the OPU up to a maximum of 1 mg.

Outcome variables
Pain assessment. A visual analogue scale (VAS) (McCormack et al., 1988Go) is a rating scale consisting of a 10 cm line oriented vertically on a paper. VAS was used to evaluate the anxiety and the abdominal pain level before OPU as well as the mean and maximum pain level during OPU and ‘pain now’ level. The measurements were performed ~30 min before OPU and directly after. Thereafter, abdominal pain was evaluated at 30 min intervals until the patient left the clinic. After discharge, patients continued abdominal pain rating approximately every 6 h for the following 24 h. VAS rating of the patient’s mean pain during the OPU was also performed by the nurse. The questionnaire had the following end-points: anxiety, i.e. no anxiety and unbearable anxiety; expected pain, abdominal pain, mean and maximum pain, and nurse pain ratings, i.e. no pain and unbearable pain.

Recorded medication, time consumption and IVF parameters. The dosage of benzodiazepine and alfentanil was recorded, and costs for acupuncture needles, benzodiazepine, alfentanil and NaCl were calculated in Euros. The time interval from the end of the OPU until discharge was recorded and referred to as time to discharge. Clinical parameters including number of previous IVF cycles, number of oocytes retrieved, number of embryos transferred per embryo transfer (ET), number of positive pregnancy tests per ET, number of gestational sacs and numbers of clinical pregnancies were recorded.

An HCG-positive pregnancy test was defined by a plasma {beta}-HCG concentration of >10 IU/l, 12 days after ET. The pregnancy rate was defined as an intrauterine gestational sac with a heartbeat 3 weeks after a positive HCG test. The implantation rate was calculated as the ratio of gestational sacs determined by ultrasound after 7 weeks in relation to the total number of embryos transferred.

Statistics
Power analysis was based on the study by Stener-Victorin et al. (1999Go). Given that the maximum pain during OPU rated on a VAS was 48.6 ± 23.1 (mean ± SD), it was calculated that 100 patients per group would provide 90% chance at a 5% significance level to detect a 30% change in pain. The Mann–Whitney U-test was used to compare differences between the groups concerning the VAS ratings. {chi}2 test was used to compare differences among groups concerning implantation rate, pregnancy rate per ET and clinical pregnancy rate. Student’s t-test for independent samples was used to compare differences between the groups concerning time in clinic and cost in Euros/OPU. P < 0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 200 patients were randomized; 100 patients were treated according to the EA regime and 100 patients received CMA (Figure 1). Demographic data did not differ between the two study groups (Table II). Both groups contained equal numbers of patients performing their first IVF trial. Once randomized, no patient was excluded or discontinued from the study.


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Table II. Demographic data of the electro-acupuncture (EA) group and the conventional medical analgesia (CMA) group
 
No significant differences between the two groups were found before OPU regarding anxiety, expected pain and abdominal pain (Table III). Directly after OPU, the EA group experienced significantly higher mean pain (P < 0.001), maximum pain (P < 0.001) as well as ‘pain now’ (P < 0.05) compared with the CMA group. At 30 min after OPU, at discharge and at the home pain ratings, there were no significant differences between the groups regarding abdominal pain (Table III). During OPU, when the nurse estimated the mean level of patients’ experienced pain, the patients’ and the nurses’ ratings were in agreement with one another (Table III).


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Table III. Visual analogue scale (VAS) ratings on vertical, 10 cm lines expressed as median (minimum–maximum) and mean (SD)
 
Patients in the EA group were hospitalized for a significantly shorter period of time when the time interval from the end of the OPU until discharge was compared between the groups (P < 0.05) (Table IV). A total of nine (9%) of the patients in the EA group were supplemented with alfentanil. The total costs in the EA group were: 23.2 Euro for acupuncture needles, 13.1 Euro for alfentanil and 1.5 Euro for NaCl; in total 36.3 Euro. The costs in the CMA group were 20.8 Euro for benzodiazepine, 131.2 Euro for alfentanil and 14.7 Euro for NaCl; in total 166.8 Euro. The total costs for the EA group were significantly lower compared with those for the CMA group (P < 0.001) (Table IV).


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Table IV. Time in clinic and costs in Euros per OPU
 
In the EA group, 100 patients underwent OPU and 88 patients had an ET. In the CMA group, 100 patients underwent OPU and 90 patients had an ET. The reasons for not performing ET were: (i) no oocytes aspirated (EA two, CMA two); (ii) no fertilization (EA six, CMA three); and (iii) no development/stagnation (EA four, CMA five). There were no significant differences between the EA and the CMA group regarding IVF/ICSI cycles (24 out of 53 versus 33 out of 44), numbers of embryos transferred (88 versus 90), numbers of HCG-positive tests (46 versus 50), pregnancy rates (52.3 versus 55.6) and implantation rates (33.8 versus 35.8).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This is, to our knowledge, the first study in which short duration EA has been used for OPU in order to obtain pain relief. The present study was set up to evaluate whether EA, when given a few minutes prior to OPU, is as effective as CMA, in an attempt to make EA more attractive for clinical use. As part of the study set-up, the CMA group was pre-medicated, whereas the EA group was not. Using this protocol, a significant per-operative difference in pain rating was found in favour of CMA.

In two previous studies by Stener-Victorin et al. (1999Go, 2003), focusing on pain relief, EA given 30 min before OPU in combination with a PCB was shown to induce as good an analgesic effect as alfentanil in combination with a PCB during OPU. Pre-medication was not used for any group in these studies. In the present study, EA patients scored significantly higher regarding mean pain, maximum pain and ‘pain now’ compared with the CMA group, but the mean and maximum pain ratings of the EA group in the present study, most interestingly, are comparable to the levels of the EA groups of the two previous studies evaluating the pain-relieving effect of EA (Stener-Victorin et al., 1999Go, 2003), showing that the difference in pain ratings most probably relies on the pre-medication of the CMA group.

Other main differences in the study design between the present study and the studies by (Stener-Victorin et al., 1999Go, 2003) are: (i) the acupuncture needles were applied a few minutes prior to the OPU in the EA group; (ii) different acupuncture points (Table I) were used; and (iii) a frequency of 20 Hz was used for electrical stimulation.

EA aims to activate the endogenous pain-controlling systems, but it is unclear exactly how long a time this activation takes. From a theoretical point of view, 30 min has been proposed to be the optimal time needed for a thorough onset of analgesia and relaxation prior to operation (Bonica, 1974Go), but this time may indeed be shorter.

The present study was performed in a Danish IVF clinic. When planning the study, we decided to use acupuncture points and EA frequencies most commonly used for gynaecological pain relief in Denmark, being aware that they differed from the Swedish protocol (Stener-Victorin et al., 1999Go, 2003). As we are still in the first phase of using acupuncture in established western modern medicine, the exact impact and significance of different acupuncture points and frequencies currently is unknown, and we are therefore still collecting data to determine the combinations.

Electrical stimulation of the acupuncture needles, i.e. EA, was given in all studies evaluating the analgesic effect during OPU, but with different frequencies. In a recent review, it was assumed that the endogenous pain-controlling systems are activated optimally when stimulated with a high frequency (80–100 Hz) or when stimulated with a combination of a low frequency (2–4 Hz) and a high frequency (80–100 Hz) (Han, 2003Go). The time to obtain the pain-relieving effect and activation of the endogenous pain-controlling system using a frequency of 20 Hz, as in the present study, has not been evaluated previously. A study comparing the different EA treatment protocols used in Sweden and Denmark, respectively, without pre-medication, is planned to clarify this point further.

The present design with the application of EA in the operating theatre without pre-treatment makes it very attractive for clinical use. Obviously this procedure is smoother for the patient with a natural continuity, when the same nurse performs the acupuncture and assists at the OPU. The time to discharge was significantly shorter for the EA group and the costs for acupuncture needles and pharmacological agents were significantly lower in the EA group compared to the CMA group.

No differences in any clinical outcome parameters between the two study groups were found. No negative side effects were reported, which is in line with previous studies under similar conditions (Wang et al., 1997Go; Stener-Victorin et al., 1999Go, 2003; Fanti et al., 2003Go).

In conclusion, a significant difference in per-operative pain rating was found in favour of CMA when using the new short duration EA set-up, most probably due to the fact that the CMA group was pre-medicated whereas the EA group were not pre-medicated as part of the study design. Despite this difference in per-operative pain rating, the procedure is well tolerated and in demand by patients. Moreover, the hospitalization time is shorter and costs are lower. At present, 50% of all OPUs at our clinic are performed using the new short duration EA protocol as an analgesic method.


    Acknowledgements
 
The authors thank the nurses who performed the EA and collected data: Kirsten Brock, Lise Sørensen, Sanne Byrum, Susanne Mailund, Ann Mari Lysdahl and Alice Mikkelsen. Without their enthusiasm and help, this study would not have been possible to perform. Moreover, acupuncturist Steen Sandrini is thanked for his competent acupuncture training of the nurses.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Bonica JJ (1974) Anesthesiology in the People’s Republic of China. Anesthesiology 40,175–186.[Medline]

Fanti L, Gemma M, Passaretti S, Guslandi M, Testoni PA, Casati A and Torri G (2003) Electroacupuncture analgesia for colonoscopy: a prospective, randomized, placebo-controlled study. Am J Gastroenterol 98,312–316.[CrossRef][Medline]

Han JS (2003) Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci 26,17–22.[CrossRef][Medline]

Kho HG, Eijk RJR, Kapteijns WMMJ and van Egmond J (1991) Acupuncture and transcutaneous stimulation analgesia in comparison with moderate-dose fentanyl anaesthesia in major surgery. Clinical efficacy and influence on recovery and morbidity. Anaesthesia 46,129–135.[Medline]

Lundeberg T and Stener-Victorin E (2002) Is there a physiological basis for the use of acupuncture in pain? Int Congress Ser 1238,3–10.[CrossRef]

McCormack HM, de L Horne DJ and Sheather S (1988) Clinical applications of visual analogue scales: a critical review. Psychol Med 8,1007–1019.

Moher D, Schulz KF and Altman DG for the CONSORT Group (2001) The CONSORT statement: revised recommendations for improving the quality of reports for parallel-group randomized trials. Ann Intern Med 134,657–662[Abstract/Free Full Text]

Soussis I, Boyd O, Paraschos T, Duffy S, Bower S, Troughton P, Lowe J et al. (1995) Follicular fluid levels of midazolam, fentanyl, and alfentanil during transvaginal oocyte retrieval. Fertil Steril 64,1003–1007.[Medline]

Stener-Victorin E, Waldenström U, Nilsson L, Wikland M and Janson PO (1999) A prospective randomized study of electro-acupuncture versus alfentanil as anaesthesia during oocyte aspiration in in-vitro fertilization. Hum Reprod 14,2480–2484.[Abstract/Free Full Text]

Stener-Victorin E, Waldenström U, Wikland M, Nilsson L, Hägglund L and Lundeberg T (2003) Electro-acupuncture as a per-operative analgesic method and its effects on implantation rate and neuropeptide Y concentrations in follicular fluid. Hum Reprod 18, 1454–1460.[Abstract/Free Full Text]

Trout SW, Hazard Vallerand AH and Kemmann E (1998) Conscious sedation for in vitro fertilization. Fertil Steril 69,799–808.[CrossRef][Medline]

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Wikland M, Evers H, Jakobsson AH, Sandqvist U and Sjoblom P (1990) The concentration of lidocaine in follicular fluid when used for paracervical block in a human IVF-ET programme. Hum Reprod 5,920–923.[Abstract]

Submitted on January 15, 2004; accepted on February 2, 2004.