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The effect of electroacupuncture on opioid-like medication consumption by chronic pain patients: A pilot randomized controlled clinical trial
Available online at www.sciencedirect.com
European Journal of Pain 12 (2008) 671–676 www.EuropeanJournalPain.com
Short Communication
The effect of electroacupuncture on opioid-like medication consumption by chronic pain patients: A pilot randomized controlled clinical trial Zhen Zheng a
a,*
, Runxiang J. Guo a, Robert D. Helme b, Andrew Muir b, Cliff Da Costa c, Charlie C.L. Xue a
Division of Chinese Medicine, School of Health Science, RMIT University, P.O. Box 71, Bundoora, Melbourne, Victoria 3083, Australia b Barbara Walker Centre for Pain Management, St. Vincent’s Hospital, Melbourne, Australia c School of Mathematical and Geospatial Sciences, RMIT University, Melbourne, Australia Received 29 April 2007; received in revised form 10 September 2007; accepted 8 October 2007 Available online 26 November 2007
Abstract Opioid-like medications (OLM) are commonly used by patients with various types of chronic pain, but their long-term benefit is questionable. Electroacupuncture (EA) has been previously shown beneficial in reducing post-operative acute OLM consumption. In this pilot randomized controlled trial, the effect of EA on OLM usage and associated side effects in chronic pain patients was evaluated. After a two-week baseline assessment, participants using OLM for their non-malignant chronic pain were randomly assigned to receive either real EA (REA, n = 17) or sham EA (SEA, n = 18) treatment twice weekly for 6 weeks before entering a 12-week follow-up. Pain, OLM consumption and their side effects were recorded daily. Participants also completed the McGill Pain Questionnaire (MPQ), SF-36 and Beck Depression Inventory (BDI) at baseline, and at the 5th, 8th, 12th, 16th and 20th week. Nine participants withdrew during the treatment period with another three during the follow-up period. Intention to treat analysis was applied. At the end of treatment period, reductions of OLM consumption in REA and SEA were 39% and 25%, respectively (p = 0.056), but this effect did not last more than 8 weeks after treatment. There was no difference between the two groups with respect to reduction of side effects and pain and the improvement of depression and quality of life. In conclusion, REA demonstrates promising short-term reduction of OLM for participants with chronic non-malignant pain, but such effect needs to be confirmed by trials with adequate sample sizes. Ó 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Electroacupuncture; Opioid-like medication; Opioid consumption; Chronic non-malignant pain; Randomized controlled trial
1. Introduction Opioid-like medications (OLM) have been frequently used to treat chronic non-malignant pain. In the USA, * Corresponding author. Tel.: +61 3 9925 7167; fax: +61 3 9925 7178. E-mail address: [email protected] (Z. Zheng).
between 1980 and 2000, opioid prescriptions for chronic musculoskeletal pain doubled, from 8% to 16% (CaudillSlosberg et al., 2004). Although the short-term effect of OLM has been supported by RCTs (Allan et al., 2001; Jamison et al., 1998; Moulin et al., 1996), the benefit of long-term opioids use for these patients is questioned. Jensen and colleagues (2006) assessed a group of patients 10 years after completion of a multidisciplinary
1090-3801/$34 Ó 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2007.10.003
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Z. Zheng et al. / European Journal of Pain 12 (2008) 671–676
pain management program, and found that patients on long-term opioids had poorer quality of life, were more depressed, and adopted passive strategies for pain management, indicating that opioids were ineffective for this group of patients. In addition, OLM are associated with unwanted side effects, such as nausea, vomiting, constipation and drowsiness, and the possibility of dose escalation (Gourlay, 1999). In Denmark, over 75% of the patients in some pain clinics used OLM, and nearly 40% of these OLM users had the potential for dependence or addiction (Breivik, 2005). Reducing OLM consumption and teaching patients how to cope with pain remain as challenges in pain management (Finlayson et al., 1986). The existing literature has provided evidence for methadone (Kennedy and Crowley, 1990; Tennant and Rawson, 1992) and integrated pain management (Currie et al., 2003 ) in reducing OLM use and improving function for chronic pain patients with opioids or substance abuse. There is, however, no literature examining any therapy that reduces OLM consumption in patients without addiction. Previous studies have shown that electroacupuncture (EA) effectively reduces acute OLM consumption by more than 60% in post-operative pain patients and the severity of pain and OLM related side effects (Lin et al., 2002; Wang et al., 1997). It is thought that such effects are achieved through enhanced release of endogenous opioid peptides (EOPs) (Cheng and Pomeranz, 1979; Han, 1989; Han et al., 1991; Han et al., 1981). The present trial aimed to examine whether real EA (REA) reduced the use of OLM consumption and associated side effects in patients with chronic pain when compared with sham EA (SEA). The study also assessed whether EA reduced the intensity of pain and improved the quality of life of these patients.
2. Methods This 20-week pilot, randomized, single blind, sham EA controlled trial was conducted with the approval from the Human Ethics Research Committees (HREC) of the RMIT University, Melbourne and the St. Vincent’s Hospital, Melbourne, Australia. The trial was conducted in 2005 and 2006 at the Barbara Walker Centre for Pain Management (BWCPM) at the St. Vincent’s Hospital, Melbourne, Australia. Written informed consent was obtained from all participants prior to the commencement of the trial. The design and conduct of the trial complied with the CONSORT statements (Moher et al., 2001). The design of the acupuncture treatment followed the Standard Recommendation in Clinical Trial of Acupuncture (STRICTA) (MacPherson et al., 2001). The methods are briefly described as follows.
2.1. Participants Pain patients aged between 18 and 80 years (inclusive), suffering from non-malignant pain for more than 3 months, and using OLM were recruited. All volunteers were assessed by pain physicians for eligibility of participation at the BWCPM according to the Classification of Chronic Pain Definitions published by the International Association for the Study of Pain (IASP) (Merskey et al., 1994) and against a set of inclusion and exclusion criteria. 2.2. Outcome measurements The primary outcome measures were the dosage of OLM, the type and incidence of related side effects, and pain intensity measured with visual analogue scales (VASs). These items were recorded daily in the Subject Diary during the baseline (1st and 2nd week) and treatment period (3rd–8th week). In addition, they were also completed daily in the 9th, 12th, 16th and 20th week during the follow-up period. To make meaningful comparison on medication use, the dosage of OLM was converted into morphine equivalence for data analysis (Margoles, 1999; Ross, 2004; Twycross, 1999). Secondary outcome measures were the McGill Pain Questionnaire (MPQ), quality of life assessed with SF36v2 Health Survey and severity of depression assessed with the Beck Depression Inventory (BDI). These assessments were completed every four weeks, that is, at the baseline, 5th, 8th, 12th, 16th and 20th week. 2.3. Interventions In the REA group, two pairs of acupuncture points, Shousanli LI10/Hegu LI4 and Zusanli ST36/Fenglong ST40, were selected unilaterally and alternated from side to side in different treatment sessions for invasive EA (Myer 501, Meyer Medical Electronics, Australia) at an alternating frequency of 2 and 100 Hz. Up to five supplementary acupuncture points were chosen according to the side effects of OLM that participants experienced during that week. In the SEA group, acupuncture needles were superficially inserted to non-classical acupuncture points with no stimulation (Vincent, 1989; Zaslawski et al., 1997) and connected to a mock EA stimulator. Either intervention was given twice a week for 6 weeks from the 3rd to the 8th week. Each treatment lasted for 30 min with a 20-min EA stimulation time. 2.4. Study procedure Fig. 1 illustrates the study procedure. During the trial period, participants were instructed to continue their routine therapies.
Z. Zheng et al. / European Journal of Pain 12 (2008) 671–676
2.5. Data analyses
82 Chronic pain patients assessed for eligibility 40 Excluded Failed to meet inclusion criteria 42 Entered baseline stage (1st to 2nd week)
35 Randomized
5 Never returned by the end of the baseline stage, 2 Scheduled for surgery
17 Allocated to the REA group (3rd to 8th week) 5 Dropped out 1 Could not tolerate the sensation of needling 1 Had aggravation of symptoms 1 Had transportation problems 1 Reason unclear 1 Had baby-sitting problems 12 Completed the treatment period
18 Allocated to the SEA group (3rd to 8th week)
9 Completed follow-up assessment (9th – 20th week)
14 Completed follow-up assessment (9th – 20th week)
4 Dropped out 2 Had transportation problems 1 Had to go back to work 1 Had a family issue 14 Completed the treatment period
3 Lost to follow up (Unable to contact)
17 Included in intention to treat analyses of the treatment effects and long term effects
673
18 Included in intention to treat analyses of the treatment effects and long term effects
Fig. 1. A flow chart of the trial procedure.
Block randomisation code was computer generated and stored in a password-protected computer. The acupuncturist was the only person who had access to the code. All outcome measures were in diary or questionnaire form. Completed diaries were returned in sealed envelopes weekly. A research assistant who was blinded to the treatment allocation checked the completion of all returned outcome measurement instruments and summarized the weekly OLM consumption. The pain physicians at the BWCPM developed OLM reduction schedules for the participants based on the summaries. A researcher, who was blinded to the treatment allocation, phoned each participant to inform them of the schedule and encouraged them to reduce OLM consumption. In total, three telephone calls were made to each participant during the 20 weeks. The success of participant’s blinding was assessed at the end of the treatment period with the Perception of EA Treatment Questionnaire (Wang et al., 1997).
All data analyses were carried out by using the Statistical Program for Social Science (SPSS, version 13.0). The demographic data, baseline data, the incidence of the OLM related side effects and the data of the Perception of EA Treatment were analysed with independent sample t-tests or v2-tests. Intention to treat analyses were employed for all outcome measures. Dosage of OLM, severity of OLM related side effects, severity of pain, and BDI data sampled at the baseline, 5th and 8th week were analysed with univariate analysis of variance (ANOVA) with repeated measures. Post hoc ttests were used whenever necessary. Follow-up data were analysed with paired t-tests within each group to detect the difference between those variables assessed at the end of the treatment and those assessed at the 16th and 20th week. Missing diary data were replaced with the last available value. Missing data of SF36 and BDI were dealt with according to the relevant manuals. The overall significance level was set at a < 0.05. An adjustment was made for multiple comparisons using the Bonferroni method.
3. Results Eighty-two chronic pain patients expressed their interest, and 47 were excluded for not meeting the inclusion criteria, being unavailable or failing to return prior to randomisation. Thirty-five patients were randomly allocated with 17 in the REA group and 18 in the SEA group. Nine participants discontinued from the trial during the treatment period; and a further three failed to return the diaries during the follow-up period. Fig. 1 lists the reasons for withdrawing from the study. 3.1. Baseline comparability The two groups were comparable for the baseline characteristics (Tables 1 and 2). The majority of participants had pain in the musculoskeletal system and took codeine, morphine, oxycodone and/or tramadol. Side effects related to OLM experienced by more than half of the participants were fatigue, drowsiness, lethargy and constipation in the REA group, and nausea, dizziness, fatigue, drowsiness, blurred vision, sedation, lethargy and anxiety in the SEA group. 3.2. Short-term effects of EA on OLM, their side effects, pain and other variables From baseline to the 8th week, the OLM consumption was significantly reduced in both treatment groups (F(2, 66) = 18.4, p < 0.001) (Table 2). The reduction was
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was statistically significantly higher at the 20th week (p = 0.022, via an adjusted significance level of 0.025) than that at the end of the treatment period (16th week: 332.8 ± 392.4; 20th week: 344.7 ± 396.8); whereas the dosage of OLM in the SEA group during the 12-week follow-up period was comparable to that at the end of the treatment (16th week: 216.5 ± 286.3; 20th week: 239.0 ± 294.5). All other measures did not show significant change during the follow-up period in either group.
Table 1 Baseline characteristics of randomized participants REA group n = 17
SEA group n = 18
Age (years) (mean ± SD)
51.1 ± 13.0
48.4 ± 10.5
Gender Male (n, %) Female (n, %)
9, 53% 8, 47%
9, 50% 9, 50%
19.8 ± 24.5
13.0 ± 11.1
10 1 4 4 6
14 0 5 3 4
Pain history (years) (mean ± SD) Types of OLM (n) Codeine Methadone Oxycodon Morphine Tramadol
a
3.4. EA safety and success of the blinding procedure A total of 345 treatment sessions were delivered, and 52 adverse events (AEs) were recorded with 19 in the SEA group and 33 in the REA group. No serious AEs were reported. Twenty-three participants completed the Perception of EA Treatment Questionnaire at the end of the treatment period. There was no statistically significant difference between the two groups, indicating successful implementation of the blinding procedure. Over 90% of the participants were willing to refer the treatment to others.
Results of independent sample t-tests and v2-test indicated there was no difference between the two groups on all of the above variables. a Note that the v2-test for this variable was affected by small frequencies in the categories.
39% in the REA group, and greater than 25% in the SEA group. The group difference in the changes over time was not statistically significant but indicated a trend toward a more rapid reduction of OLM in the REA group (F(2, 66) = 3.0, p = 0.056). Total incidents of side effects associated with OLM were reduced by 40% and 45% in the REA and SEA groups, respectively. Group differences were not detected in the intensity of pain, duration of pain, depression and QoL measures. For those who completed the six-week treatment, OLM was reduced in the REA and SEA groups by 64% and 46% (126.1 ± 97.3 mg vs 113.9 ± 129.2 mg at the end of the 8th week), respectively.
4. Discussion This pilot randomized controlled trial demonstrated that both REA and SEA significantly reduced OLM consumption over 6 weeks of treatment. There was a positive trend in that participants in the REA group experienced a more rapid reduction of OLM consumption. This effect was short-term and maintained for 8 weeks after treatment. Considerable efforts were made to ensure the effective execution of the trial protocol such as implementation of a SEA group and the successful blinding of participants and the researchers. The characteristics of the study
3.3. Follow-up The weekly dosages of OLM in the REA group increased gradually during the follow-up period, and
Table 2 ANOVA analyses of intention to treat data of primary and secondary outcome measures Baseline 1st and 2nd week
5th week
8th week
Time effect
Group by time interaction
OLM consumption (mg/week) REA 461.6 ± 462.6 SEA 295.5 ± 288.0
361.9 ± 403.3 234.7 ± 292.9
281.4 ± 401.9 219.1 ± 293.0
F(2,66)a = 18.4 P < .001
F(2,66) = 3.0 P = .056
OLM related side effects: incidents REA 92 SEA 118
52 80
55 66
Average pain REA 4.6 ±1.6 SEA 5.5 ± 1.7
3.7 ± 1.9 4.7 ± 1.7
3.8 ± 2.0 4.8 ± 1.9
F(2,66) = 8.4 P = .001
F(2,66) = .04 P = .960
Duration of pain (hr/day) REA 16.8 ± 5.3 SEA 15.6 ± 4.6
15.7 ± 6.2 14.8 ± 4.0
16.4 ± 5.8 14.6 ± 4.5
F(2,66) = 1.5 P = .234
F(2,66) = .4 P = .675
a
Degree of freedom.
Z. Zheng et al. / European Journal of Pain 12 (2008) 671–676
population were similar to general chronic musculoskeletal patients with respect to the dosages and types of OLM, incidence of OLM related side effects (Kalso et al., 2004) and levels of pain (Cowan et al., 2005). Significant limitations of this study included the unequal OLM dosage at baseline between the REA and SEA groups and, in particular, the small sample size. At baseline, the REA group was consuming 36% more of OLM than the SEA group. As a result, a repeated measures ANOVA was used to examine the group by time interaction rather than a t-tests to assess the group difference at the end of the treatment period. However, the possibility that a higher OLM consumption made it easy for the participants to reduce the dosage cannot be excluded. The sample size of 35 participants was smaller than anticipated. The observed power of group by time interaction was 56.4%. Based on the current data, to detect a 14% group difference in OLM reduction, with 80% power and a significance level at 0.05, 216 participants would be needed. The 64% reduction of OLM in the REA group of those who completed the treatment period is consistent with a decrease of 38–65% reported in previous studies on EA and acute OLM requirement (Chen et al., 1998; Lin et al., 2002; Wang et al., 1997), although the types and dosage of OLM for chronic pain and post-operative pain cannot be directly compared. The 46% reduction in SEA group is, however, higher than the 21–23% reduction reported in post-operative studies. This is likely due to the potent non-specific effects of sham needling procedures (Sa´nchez-Araujo, 1998; ter Riet et al., 1998; Vincent and Richardson, 1986). Many clinical studies show that sham needling reduces pain and improves quality of life and depression as well as real acupuncture does (Assefi et al., 2005; Linde et al., 2005; Scharf et al., 2006; Witt et al., 2005; Witt et al., 2006; Zhu and Polus, 2002). In addition, the encouragement from the third researcher, a strategy not employed in the previous studies, might have been viewed positively by the participants. Indeed, in some pain management clinics, encouragement is the only method to assist patients to reduce OLM prior to a cognitive behavioural therapy program (Bradbury, 2003). Because a non-acupuncture group was not included, the exact effect of verbal encouragement cannot be determined. An unexpected finding of the trial is that the effect of REA on OLM reduction appeared to be short-lasting for up to 8 weeks after treatment whereas the effect of SEA was sustained throughout the 12-week follow-up period. It appears logical that discontinuation of EA stimulation would lead to a reduction of EOPs released, and OLM consumption would therefore increase as seen in the REA group in the current study. The long-term benefit of SEA might be due to non-specific effects of EA or other unknown factors.
675
EA is well tolerated by the majority of participants and there were only two withdrawals due to reported mild adverse effects. Types of AEs reported are consistent with those reported by previous acupuncture clinical trials and surveys (White et al., 2001; Witt et al., 2006). The current pilot trial shows that EA could be an effective and safe approach to reduce opioid consumption and OLM related side effects in the short-term. Although underpowered, as the first study that attempted to examine the use of EA for OLM reduction in chronic pain patients, it provides critical data on the potential EA effect for future trials. Future studies should recruit a large sample of participants, preferably chronic pain sufferers from the community, and include a non-acupuncture group receiving verbal encouragement only. Acknowledgements The study was supported by a Research Grant provided by the then Faculty of Life Sciences, RMIT University. Ms. Jessica Guo, a research candidate, was supported by an Australian Postgraduate Award (APA) and an Australian Acupuncture and Chinese Medicine Association (AACMA) Research Grant 2005. The authors thank all the participants for their effort and time. The authors also appreciate the assistance and advice given by Dr. Jane Trinca, Ms. Jean Bradbury, Ms. Shelley Colman, Ms. Kathryn Kirkwood and other staff at the Barbara Walker Centre for Pain Management, and thank Ms. Yanyi Wang for data checking and entry.
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European Journal of Pain 12 (2008) 671–676 www.EuropeanJournalPain.com
Short Communication
The effect of electroacupuncture on opioid-like medication consumption by chronic pain patients: A pilot randomized controlled clinical trial Zhen Zheng a
a,*
, Runxiang J. Guo a, Robert D. Helme b, Andrew Muir b, Cliff Da Costa c, Charlie C.L. Xue a
Division of Chinese Medicine, School of Health Science, RMIT University, P.O. Box 71, Bundoora, Melbourne, Victoria 3083, Australia b Barbara Walker Centre for Pain Management, St. Vincent’s Hospital, Melbourne, Australia c School of Mathematical and Geospatial Sciences, RMIT University, Melbourne, Australia Received 29 April 2007; received in revised form 10 September 2007; accepted 8 October 2007 Available online 26 November 2007
Abstract Opioid-like medications (OLM) are commonly used by patients with various types of chronic pain, but their long-term benefit is questionable. Electroacupuncture (EA) has been previously shown beneficial in reducing post-operative acute OLM consumption. In this pilot randomized controlled trial, the effect of EA on OLM usage and associated side effects in chronic pain patients was evaluated. After a two-week baseline assessment, participants using OLM for their non-malignant chronic pain were randomly assigned to receive either real EA (REA, n = 17) or sham EA (SEA, n = 18) treatment twice weekly for 6 weeks before entering a 12-week follow-up. Pain, OLM consumption and their side effects were recorded daily. Participants also completed the McGill Pain Questionnaire (MPQ), SF-36 and Beck Depression Inventory (BDI) at baseline, and at the 5th, 8th, 12th, 16th and 20th week. Nine participants withdrew during the treatment period with another three during the follow-up period. Intention to treat analysis was applied. At the end of treatment period, reductions of OLM consumption in REA and SEA were 39% and 25%, respectively (p = 0.056), but this effect did not last more than 8 weeks after treatment. There was no difference between the two groups with respect to reduction of side effects and pain and the improvement of depression and quality of life. In conclusion, REA demonstrates promising short-term reduction of OLM for participants with chronic non-malignant pain, but such effect needs to be confirmed by trials with adequate sample sizes. Ó 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Electroacupuncture; Opioid-like medication; Opioid consumption; Chronic non-malignant pain; Randomized controlled trial
1. Introduction Opioid-like medications (OLM) have been frequently used to treat chronic non-malignant pain. In the USA, * Corresponding author. Tel.: +61 3 9925 7167; fax: +61 3 9925 7178. E-mail address: [email protected] (Z. Zheng).
between 1980 and 2000, opioid prescriptions for chronic musculoskeletal pain doubled, from 8% to 16% (CaudillSlosberg et al., 2004). Although the short-term effect of OLM has been supported by RCTs (Allan et al., 2001; Jamison et al., 1998; Moulin et al., 1996), the benefit of long-term opioids use for these patients is questioned. Jensen and colleagues (2006) assessed a group of patients 10 years after completion of a multidisciplinary
1090-3801/$34 Ó 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2007.10.003
672
Z. Zheng et al. / European Journal of Pain 12 (2008) 671–676
pain management program, and found that patients on long-term opioids had poorer quality of life, were more depressed, and adopted passive strategies for pain management, indicating that opioids were ineffective for this group of patients. In addition, OLM are associated with unwanted side effects, such as nausea, vomiting, constipation and drowsiness, and the possibility of dose escalation (Gourlay, 1999). In Denmark, over 75% of the patients in some pain clinics used OLM, and nearly 40% of these OLM users had the potential for dependence or addiction (Breivik, 2005). Reducing OLM consumption and teaching patients how to cope with pain remain as challenges in pain management (Finlayson et al., 1986). The existing literature has provided evidence for methadone (Kennedy and Crowley, 1990; Tennant and Rawson, 1992) and integrated pain management (Currie et al., 2003 ) in reducing OLM use and improving function for chronic pain patients with opioids or substance abuse. There is, however, no literature examining any therapy that reduces OLM consumption in patients without addiction. Previous studies have shown that electroacupuncture (EA) effectively reduces acute OLM consumption by more than 60% in post-operative pain patients and the severity of pain and OLM related side effects (Lin et al., 2002; Wang et al., 1997). It is thought that such effects are achieved through enhanced release of endogenous opioid peptides (EOPs) (Cheng and Pomeranz, 1979; Han, 1989; Han et al., 1991; Han et al., 1981). The present trial aimed to examine whether real EA (REA) reduced the use of OLM consumption and associated side effects in patients with chronic pain when compared with sham EA (SEA). The study also assessed whether EA reduced the intensity of pain and improved the quality of life of these patients.
2. Methods This 20-week pilot, randomized, single blind, sham EA controlled trial was conducted with the approval from the Human Ethics Research Committees (HREC) of the RMIT University, Melbourne and the St. Vincent’s Hospital, Melbourne, Australia. The trial was conducted in 2005 and 2006 at the Barbara Walker Centre for Pain Management (BWCPM) at the St. Vincent’s Hospital, Melbourne, Australia. Written informed consent was obtained from all participants prior to the commencement of the trial. The design and conduct of the trial complied with the CONSORT statements (Moher et al., 2001). The design of the acupuncture treatment followed the Standard Recommendation in Clinical Trial of Acupuncture (STRICTA) (MacPherson et al., 2001). The methods are briefly described as follows.
2.1. Participants Pain patients aged between 18 and 80 years (inclusive), suffering from non-malignant pain for more than 3 months, and using OLM were recruited. All volunteers were assessed by pain physicians for eligibility of participation at the BWCPM according to the Classification of Chronic Pain Definitions published by the International Association for the Study of Pain (IASP) (Merskey et al., 1994) and against a set of inclusion and exclusion criteria. 2.2. Outcome measurements The primary outcome measures were the dosage of OLM, the type and incidence of related side effects, and pain intensity measured with visual analogue scales (VASs). These items were recorded daily in the Subject Diary during the baseline (1st and 2nd week) and treatment period (3rd–8th week). In addition, they were also completed daily in the 9th, 12th, 16th and 20th week during the follow-up period. To make meaningful comparison on medication use, the dosage of OLM was converted into morphine equivalence for data analysis (Margoles, 1999; Ross, 2004; Twycross, 1999). Secondary outcome measures were the McGill Pain Questionnaire (MPQ), quality of life assessed with SF36v2 Health Survey and severity of depression assessed with the Beck Depression Inventory (BDI). These assessments were completed every four weeks, that is, at the baseline, 5th, 8th, 12th, 16th and 20th week. 2.3. Interventions In the REA group, two pairs of acupuncture points, Shousanli LI10/Hegu LI4 and Zusanli ST36/Fenglong ST40, were selected unilaterally and alternated from side to side in different treatment sessions for invasive EA (Myer 501, Meyer Medical Electronics, Australia) at an alternating frequency of 2 and 100 Hz. Up to five supplementary acupuncture points were chosen according to the side effects of OLM that participants experienced during that week. In the SEA group, acupuncture needles were superficially inserted to non-classical acupuncture points with no stimulation (Vincent, 1989; Zaslawski et al., 1997) and connected to a mock EA stimulator. Either intervention was given twice a week for 6 weeks from the 3rd to the 8th week. Each treatment lasted for 30 min with a 20-min EA stimulation time. 2.4. Study procedure Fig. 1 illustrates the study procedure. During the trial period, participants were instructed to continue their routine therapies.
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2.5. Data analyses
82 Chronic pain patients assessed for eligibility 40 Excluded Failed to meet inclusion criteria 42 Entered baseline stage (1st to 2nd week)
35 Randomized
5 Never returned by the end of the baseline stage, 2 Scheduled for surgery
17 Allocated to the REA group (3rd to 8th week) 5 Dropped out 1 Could not tolerate the sensation of needling 1 Had aggravation of symptoms 1 Had transportation problems 1 Reason unclear 1 Had baby-sitting problems 12 Completed the treatment period
18 Allocated to the SEA group (3rd to 8th week)
9 Completed follow-up assessment (9th – 20th week)
14 Completed follow-up assessment (9th – 20th week)
4 Dropped out 2 Had transportation problems 1 Had to go back to work 1 Had a family issue 14 Completed the treatment period
3 Lost to follow up (Unable to contact)
17 Included in intention to treat analyses of the treatment effects and long term effects
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18 Included in intention to treat analyses of the treatment effects and long term effects
Fig. 1. A flow chart of the trial procedure.
Block randomisation code was computer generated and stored in a password-protected computer. The acupuncturist was the only person who had access to the code. All outcome measures were in diary or questionnaire form. Completed diaries were returned in sealed envelopes weekly. A research assistant who was blinded to the treatment allocation checked the completion of all returned outcome measurement instruments and summarized the weekly OLM consumption. The pain physicians at the BWCPM developed OLM reduction schedules for the participants based on the summaries. A researcher, who was blinded to the treatment allocation, phoned each participant to inform them of the schedule and encouraged them to reduce OLM consumption. In total, three telephone calls were made to each participant during the 20 weeks. The success of participant’s blinding was assessed at the end of the treatment period with the Perception of EA Treatment Questionnaire (Wang et al., 1997).
All data analyses were carried out by using the Statistical Program for Social Science (SPSS, version 13.0). The demographic data, baseline data, the incidence of the OLM related side effects and the data of the Perception of EA Treatment were analysed with independent sample t-tests or v2-tests. Intention to treat analyses were employed for all outcome measures. Dosage of OLM, severity of OLM related side effects, severity of pain, and BDI data sampled at the baseline, 5th and 8th week were analysed with univariate analysis of variance (ANOVA) with repeated measures. Post hoc ttests were used whenever necessary. Follow-up data were analysed with paired t-tests within each group to detect the difference between those variables assessed at the end of the treatment and those assessed at the 16th and 20th week. Missing diary data were replaced with the last available value. Missing data of SF36 and BDI were dealt with according to the relevant manuals. The overall significance level was set at a < 0.05. An adjustment was made for multiple comparisons using the Bonferroni method.
3. Results Eighty-two chronic pain patients expressed their interest, and 47 were excluded for not meeting the inclusion criteria, being unavailable or failing to return prior to randomisation. Thirty-five patients were randomly allocated with 17 in the REA group and 18 in the SEA group. Nine participants discontinued from the trial during the treatment period; and a further three failed to return the diaries during the follow-up period. Fig. 1 lists the reasons for withdrawing from the study. 3.1. Baseline comparability The two groups were comparable for the baseline characteristics (Tables 1 and 2). The majority of participants had pain in the musculoskeletal system and took codeine, morphine, oxycodone and/or tramadol. Side effects related to OLM experienced by more than half of the participants were fatigue, drowsiness, lethargy and constipation in the REA group, and nausea, dizziness, fatigue, drowsiness, blurred vision, sedation, lethargy and anxiety in the SEA group. 3.2. Short-term effects of EA on OLM, their side effects, pain and other variables From baseline to the 8th week, the OLM consumption was significantly reduced in both treatment groups (F(2, 66) = 18.4, p < 0.001) (Table 2). The reduction was
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was statistically significantly higher at the 20th week (p = 0.022, via an adjusted significance level of 0.025) than that at the end of the treatment period (16th week: 332.8 ± 392.4; 20th week: 344.7 ± 396.8); whereas the dosage of OLM in the SEA group during the 12-week follow-up period was comparable to that at the end of the treatment (16th week: 216.5 ± 286.3; 20th week: 239.0 ± 294.5). All other measures did not show significant change during the follow-up period in either group.
Table 1 Baseline characteristics of randomized participants REA group n = 17
SEA group n = 18
Age (years) (mean ± SD)
51.1 ± 13.0
48.4 ± 10.5
Gender Male (n, %) Female (n, %)
9, 53% 8, 47%
9, 50% 9, 50%
19.8 ± 24.5
13.0 ± 11.1
10 1 4 4 6
14 0 5 3 4
Pain history (years) (mean ± SD) Types of OLM (n) Codeine Methadone Oxycodon Morphine Tramadol
a
3.4. EA safety and success of the blinding procedure A total of 345 treatment sessions were delivered, and 52 adverse events (AEs) were recorded with 19 in the SEA group and 33 in the REA group. No serious AEs were reported. Twenty-three participants completed the Perception of EA Treatment Questionnaire at the end of the treatment period. There was no statistically significant difference between the two groups, indicating successful implementation of the blinding procedure. Over 90% of the participants were willing to refer the treatment to others.
Results of independent sample t-tests and v2-test indicated there was no difference between the two groups on all of the above variables. a Note that the v2-test for this variable was affected by small frequencies in the categories.
39% in the REA group, and greater than 25% in the SEA group. The group difference in the changes over time was not statistically significant but indicated a trend toward a more rapid reduction of OLM in the REA group (F(2, 66) = 3.0, p = 0.056). Total incidents of side effects associated with OLM were reduced by 40% and 45% in the REA and SEA groups, respectively. Group differences were not detected in the intensity of pain, duration of pain, depression and QoL measures. For those who completed the six-week treatment, OLM was reduced in the REA and SEA groups by 64% and 46% (126.1 ± 97.3 mg vs 113.9 ± 129.2 mg at the end of the 8th week), respectively.
4. Discussion This pilot randomized controlled trial demonstrated that both REA and SEA significantly reduced OLM consumption over 6 weeks of treatment. There was a positive trend in that participants in the REA group experienced a more rapid reduction of OLM consumption. This effect was short-term and maintained for 8 weeks after treatment. Considerable efforts were made to ensure the effective execution of the trial protocol such as implementation of a SEA group and the successful blinding of participants and the researchers. The characteristics of the study
3.3. Follow-up The weekly dosages of OLM in the REA group increased gradually during the follow-up period, and
Table 2 ANOVA analyses of intention to treat data of primary and secondary outcome measures Baseline 1st and 2nd week
5th week
8th week
Time effect
Group by time interaction
OLM consumption (mg/week) REA 461.6 ± 462.6 SEA 295.5 ± 288.0
361.9 ± 403.3 234.7 ± 292.9
281.4 ± 401.9 219.1 ± 293.0
F(2,66)a = 18.4 P < .001
F(2,66) = 3.0 P = .056
OLM related side effects: incidents REA 92 SEA 118
52 80
55 66
Average pain REA 4.6 ±1.6 SEA 5.5 ± 1.7
3.7 ± 1.9 4.7 ± 1.7
3.8 ± 2.0 4.8 ± 1.9
F(2,66) = 8.4 P = .001
F(2,66) = .04 P = .960
Duration of pain (hr/day) REA 16.8 ± 5.3 SEA 15.6 ± 4.6
15.7 ± 6.2 14.8 ± 4.0
16.4 ± 5.8 14.6 ± 4.5
F(2,66) = 1.5 P = .234
F(2,66) = .4 P = .675
a
Degree of freedom.
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population were similar to general chronic musculoskeletal patients with respect to the dosages and types of OLM, incidence of OLM related side effects (Kalso et al., 2004) and levels of pain (Cowan et al., 2005). Significant limitations of this study included the unequal OLM dosage at baseline between the REA and SEA groups and, in particular, the small sample size. At baseline, the REA group was consuming 36% more of OLM than the SEA group. As a result, a repeated measures ANOVA was used to examine the group by time interaction rather than a t-tests to assess the group difference at the end of the treatment period. However, the possibility that a higher OLM consumption made it easy for the participants to reduce the dosage cannot be excluded. The sample size of 35 participants was smaller than anticipated. The observed power of group by time interaction was 56.4%. Based on the current data, to detect a 14% group difference in OLM reduction, with 80% power and a significance level at 0.05, 216 participants would be needed. The 64% reduction of OLM in the REA group of those who completed the treatment period is consistent with a decrease of 38–65% reported in previous studies on EA and acute OLM requirement (Chen et al., 1998; Lin et al., 2002; Wang et al., 1997), although the types and dosage of OLM for chronic pain and post-operative pain cannot be directly compared. The 46% reduction in SEA group is, however, higher than the 21–23% reduction reported in post-operative studies. This is likely due to the potent non-specific effects of sham needling procedures (Sa´nchez-Araujo, 1998; ter Riet et al., 1998; Vincent and Richardson, 1986). Many clinical studies show that sham needling reduces pain and improves quality of life and depression as well as real acupuncture does (Assefi et al., 2005; Linde et al., 2005; Scharf et al., 2006; Witt et al., 2005; Witt et al., 2006; Zhu and Polus, 2002). In addition, the encouragement from the third researcher, a strategy not employed in the previous studies, might have been viewed positively by the participants. Indeed, in some pain management clinics, encouragement is the only method to assist patients to reduce OLM prior to a cognitive behavioural therapy program (Bradbury, 2003). Because a non-acupuncture group was not included, the exact effect of verbal encouragement cannot be determined. An unexpected finding of the trial is that the effect of REA on OLM reduction appeared to be short-lasting for up to 8 weeks after treatment whereas the effect of SEA was sustained throughout the 12-week follow-up period. It appears logical that discontinuation of EA stimulation would lead to a reduction of EOPs released, and OLM consumption would therefore increase as seen in the REA group in the current study. The long-term benefit of SEA might be due to non-specific effects of EA or other unknown factors.
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EA is well tolerated by the majority of participants and there were only two withdrawals due to reported mild adverse effects. Types of AEs reported are consistent with those reported by previous acupuncture clinical trials and surveys (White et al., 2001; Witt et al., 2006). The current pilot trial shows that EA could be an effective and safe approach to reduce opioid consumption and OLM related side effects in the short-term. Although underpowered, as the first study that attempted to examine the use of EA for OLM reduction in chronic pain patients, it provides critical data on the potential EA effect for future trials. Future studies should recruit a large sample of participants, preferably chronic pain sufferers from the community, and include a non-acupuncture group receiving verbal encouragement only. Acknowledgements The study was supported by a Research Grant provided by the then Faculty of Life Sciences, RMIT University. Ms. Jessica Guo, a research candidate, was supported by an Australian Postgraduate Award (APA) and an Australian Acupuncture and Chinese Medicine Association (AACMA) Research Grant 2005. The authors thank all the participants for their effort and time. The authors also appreciate the assistance and advice given by Dr. Jane Trinca, Ms. Jean Bradbury, Ms. Shelley Colman, Ms. Kathryn Kirkwood and other staff at the Barbara Walker Centre for Pain Management, and thank Ms. Yanyi Wang for data checking and entry.
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