Abstract

Objective. To study if acupuncture, combined with ondansetron treatment, reduces nausea and vomiting associated with cyclophosphamide infusion in patients with rheumatic diseases.

Methods. Thirty-nine patients were treated with acupuncture at point PC 6 and/or in the ear to decrease nausea and vomiting. The patients reported the severity of nausea and number of bouts of vomiting at the start of chemotherapy and after 4, 8, 24, 48 and 72 h.

Results. Compared with ondansetron treatment alone, the combined acupuncture–ondansetron treatment significantly decreased both the severity of nausea and the number of bouts of vomiting 24 and 48 h after the subjects had received acupuncture at the first treatment session (nausea: P < 0.0001; vomiting: P < 0.0035). Nearly the same results were seen 48 and 72 h after the subjects had had their last treatment of acupuncture (nausea P < 0.0080). Similar results were found after 24 to 48 h, when a comparison was made between two sessions close in time (nausea: P < 0.0001 after 24 h, P < 0.0003 after 48 h; vomiting: P < 0.0007).

Conclusions. Our results clearly indicate that combined treatment with acupuncture and ondansetron reduces the severity and the duration of chemotherapy-induced nausea as well as the number of bouts of vomiting as compared with ondansetron therapy alone, in patients with rheumatic diseases.

Acupuncture is a scientifically accepted method for treating pain [1]. It has also been shown to reduce nausea effectively in seasickness and morning sickness during pregnancy, as well as in patients pre-medicated with opioids before surgery [25].

Nausea of varying intensity is a very common side-effect of chemotherapy. Dundee et al. [4] reported that 96% of their patients felt sick after the first chemotherapy treatment, that the feeling of sickness is likely to accompany any subsequent drug administration, and that tolerance did not appear to develop to the side-effects of cancer chemotherapy agents. They found that acupuncture administered at point PC 6 (‘Neiguan’) significantly improved nausea in 97% of the 130 cancer patients studied. This effect was absent when a placebo point was tested.

To determine if the beneficial effect on nausea attributed to acupuncture is due to non-specific effects of attention and clinician–patient interaction, Shen et al. [6] performed a three-arm randomized controlled trial in 104 patients with high-risk breast cancer. Studying the effects of electroacupuncture during 5 days of chemotherapy and a 9-day follow-up period, they found that electroacupuncture was more effective in controlling emesis than minimal needling or anti-emetic pharmacotherapy alone. However, the observed effect had a limited duration and the differences between the groups were not significant at 9-day follow-up.

A review by Mayer [5] showed that acupuncture as a treatment in general is useful, and presented evidence that acupuncture is effective for treatment of chemotherapy-induced nausea and vomiting in cancer patients.

Patients with rheumatic diseases are nowadays also often treated with immunosuppressive drugs [7]. This includes patients with extra-articular rheumatoid arthritis (RA), Wegener’s granulomatosis and other primary vasculitides, systemic lupus erythematosus (SLE), scleroderma and mixed connective tissue disease (MCTD). Immunomodulating treatment is used primarily to suppress the activity of the disease by down-regulation of the proliferation of immunocompetent cells and the secretion of pro-inflammatory cytokines, such as interleukin 1 and tumour necrosis factor-α [7].

The side-effects of cyclophosphamide treatment, an alkylating agent frequently used in cases of severe rheumatic disease, are dose dependent. Cells of the bone marrow and the mucous membranes of the intestines and the urinary bladder are especially sensitive to the action of cyclophosphamide [7]. Delayed nausea and vomiting in connection with cyclophosphamide treatment are commonly observed in clinical practice. Some patients suffer from nausea just once, while the majority may have severe symptoms for several days after each treatment. To relieve this side-effect, patients are given anti-emetic drugs such as ondansetron. In spite of this anti-emetic treatment, many patients still suffer from severe nausea and vomiting.

To our knowledge, no studies have investigated the effects of acupuncture on nausea and vomiting in patients with rheumatic diseases receiving chemotherapy on repeated occasions over a long period of time. Results from the cancer studies mentioned above are not necessarily directly applicable to patients with rheumatic diseases. Furthermore, in those studies patients were treated on only one occasion or during one period.

Originally we intended to randomize the patients into two treatment groups, one receiving acupuncture and no ondansetron and the other both acupuncture and ondansetron. However, randomization did not succeed since almost all patients clearly expressed a wish to have a combined acupuncture and ondansetron treatment.

The aim of this study was thus to investigate the effect of acupuncture in combination with ondansetron on nausea and vomiting in patients with severe rheumatic diseases treated with chemotherapy.

Patients and methods

Patients

An increasing number of patients with rheumatic diseases are treated with intravenous chemotherapy throughout the world. The immunomodulating medication, mainly cyclophosphamide, is used in lower doses than is employed for cancer treatment. The dose level is usually between 750 and 1500 mg, depending on the patient’s weight and need of immunosuppression. The treatment, so-called intermittent pulse treatment, is mostly administered as one infusion once a month for 4 months up to 2 yr, depending on the activity of the disease/exacerbation and on the rapidity of the clinical response to the treatment.

Consecutive in-patients at the department of rheumatology with the diagnosis of SLE, RA, MCTD, primary vasculitis or other rheumatic systemic diseases with pulmonary or nephritic manifestations were invited to participate in the study and offered acupuncture as an additional treatment against nausea.

The inclusion criterion was a prior session with cyclophosphamide followed by experience of nausea despite simultaneous treatment with ondansetron. Exclusion criteria were severe psychiatric illness, sensitivity to needlesticks owing to hyperaesthesia or prolonged bleeding time, or lymphatic oedema in the arms.

The patients who agreed to participate in the study were contacted by one of the authors and asked to fill in a study protocol at every session of chemotherapy. All patients were informed about the experiences of acupuncture as a treatment in general and its possible beneficial effect on nausea.

Seventy-six patients entered the study and 39 completed it. Fifteen patients who had acupuncture treatment only once or twice were excluded from the study because cyclophosphamide treatment was terminated owing to lack of effect on the underlying illness. In addition, 16 of the patients who had tried acupuncture treatment once or twice did not consider their nausea to be troublesome enough to continue the acupuncture and were therefore excluded from the study. Six patients dropped out without providing any reason.

Of the 39 patients who completed the study, 32 were women and seven men. The median age was 47 yr (range 21–72). Thirteen patients had SLE, 11 had primary vasculitis, four MCTD, six scleroderma and five persons RA with either amyloidosis or secondary necrotizing vasculitis.

Methods

The pre-experimental pretest–posttest design was used. Such a design enables questions to be answered over time by performing a pretest before the independent variable is introduced. If the probands are tested both before and after the procedure, it is possible to assess a difference in the results of the dependent variable.

A pilot study comprising 10 patients was first conducted to test the method and the protocol. This resulted in some changes in the protocol to make it easier for the patients to fill in.

The patients filled in the number of bouts of vomiting and rated the degree of nausea on a four-step scale (0 = no nausea, 1 = slight nausea, 2 = moderate nausea and 3 = severe nausea) at the start of the infusion and after 4, 8, 24, 48 and 72 h. The three observation times of the first 24 h were chosen after other studies, but as cyclophosphamide is known to give a delayed sickness, observations of 48 and 72 h after the infusion were added.

The following information was entered into the study protocol from the patients’ records: date of treatment, dose of cyclophosphamide, diagnosis and consecutive treatment number. The acupuncture points, and time and duration of acupuncture were also noted.

The acupuncture points chosen were the PC 6 (‘Neiguan’) and/or two acupuncture points in the ear (‘Lung’ and ‘Liver’). These points are considered to be equal in their effect on nausea. The needles were inserted into the patients unilaterally or bilaterally at least 15–30 min before the cyclophosphamide infusion was started. The normal time for acupuncture was 30–45 min. Stimulation was made so ‘De Qi’ (the needle sensation in most cases described as a complex feeling of numbness, pressure, tenderness and warmth/cold) was achieved when inserting and removing the needles, but not in-between.

An experimental design of the study is outlined in Fig. 1. The patients were included in all four groups, depending on the acupuncture treatment (phase 1–6).

Fig. 1.

The flow chart of analyses made on 39 patients with rheumatic diseases who have undergone a series of chemotherapy treatments with and without acupuncture.

Fig. 1.

The flow chart of analyses made on 39 patients with rheumatic diseases who have undergone a series of chemotherapy treatments with and without acupuncture.

Phase 1. The patients underwent 1–3 sessions of chemotherapy without acupuncture treatment, and severity of nausea and bouts of vomiting were measured.

Phase 2. First session of chemotherapy with acupuncture and the same registrations of side-effects were measured. This could in some cases mean that the time interval between the first time of chemotherapy without acupuncture and the first time with acupuncture could vary from 4–6 weeks up to 3 months.

Phase 3. The severity of nausea and bouts of vomiting were followed during a series of chemotherapy treatments combined with acupuncture treatment, but were not included in the analysis. The number of treatments varied between 1 and 5 and was determined by practical clinical reasons.

Phase 4. One to two chemotherapy treatments without acupuncture were then provided again, as the intention was to make extra comparisons with phases 1, 2 and 3.

Phase 5. Further sessions of chemotherapy combined with acupuncture treatment then followed. The number of treatments varied between 3 and 24 and depended on how many sessions of chemotherapy the patients were undergoing (based on the response of the disease to the treatment).

Phase 6. The last session of chemotherapy treatment with acupuncture was registered.

Analysis 1. A comparison of the data of these observations (phase 1 and phase 2) was made. If more than one session was notified in phase 1, the analysis of the first one was used.

Analysis 2. A comparison between data from phase 3 and phase 4 was made. In phase 3 the last session of acupuncture was chosen and the first of no acupuncture in phase 4.

Analysis 3. Data from phase 1 were compared with data from phase 6.

Analysis 4. Data from phase 2 were compared with data from phase 6.

Every session of chemotherapy was administered once every 4–6 weeks. Study protocols were distributed each time the patients received chemotherapy treatment. The protocols were brought back at the time of the next chemotherapy session or sent by post 10 days after chemotherapy, in connection with blood tests.

Statistical methods

Wilcoxon’s signed rank sum test [8] for paired observations was used for testing differences between different treatments of the patient group.

Discrete data (degree of nausea) were presented as frequencies and the distribution of variables of continuous data (number of bouts of vomiting) was presented as means, medians and range.

Ethical considerations

It was not necessary to obtain ethical approval from the Research Ethic's Committee, as this study was an evaluation of a common clinical treatment. The patients were informed about the study and gave their consent verbally.

Results

Acupuncture significantly reduced the severity, especially the duration, of nausea, as well as the number of bouts of vomiting following cyclophosphamide after 24 to 48 h. The number of bouts of vomiting was significantly reduced at the first session of acupuncture (Table 1). The same results could also be seen when the interim between treatments (ondansetron alone vs acupuncture–ondansetron combined) was short (within 4–6 weeks) and when the patients’ health status was considered more stable (Table 2).

Table 1.

Impact of acupuncture on severity of nausea and number of bouts of vomiting in rheumatic patients on chemotherapy (n = 39) at the first session of acupuncture

Time after cyclophosphamide infusion Nausea (0–3) No acupuncture No. (%) Acupuncture No. (%) Comparison: no acupuncture/acupuncture (P value) 
After 24 h 3 (7.7) 10 (25.6) 0.0001 
 9 (23.1) 18 (46.2)  
 10 (25.6) 3 (7.7)  
 17 (43.6) 8 (20.5)  
After 48 h 5 (12.8) 21 (53.9) 0.0001 
 7 (18.0) 11 (28.2)  
 10 (25.6) 4 (10.3)  
 17 (43.6) 3 (7.7)  
After 72 h 12 (30.8) 23 (59.0) 0.0106 
 10 (25.6) 8 (20.5)  
 9 (23.1) 6 (15.4)  
 8 (20.5) 2 (5.1)  
 No. of bouts of vomiting    
 21 (53.9) 31 (79.5) 0.0035 
 1–4 8 (20.5) 6 (15.4)  
 5–9 6 (15.4) 2 (5.1)  
 10–25 4 (10.3) 0 (0)  
    Differences 
Mean  3.33 0.59 –2.74 
Median (range)  0 (0–25) 0 (0–7) 0 (–25, 7) 
Time after cyclophosphamide infusion Nausea (0–3) No acupuncture No. (%) Acupuncture No. (%) Comparison: no acupuncture/acupuncture (P value) 
After 24 h 3 (7.7) 10 (25.6) 0.0001 
 9 (23.1) 18 (46.2)  
 10 (25.6) 3 (7.7)  
 17 (43.6) 8 (20.5)  
After 48 h 5 (12.8) 21 (53.9) 0.0001 
 7 (18.0) 11 (28.2)  
 10 (25.6) 4 (10.3)  
 17 (43.6) 3 (7.7)  
After 72 h 12 (30.8) 23 (59.0) 0.0106 
 10 (25.6) 8 (20.5)  
 9 (23.1) 6 (15.4)  
 8 (20.5) 2 (5.1)  
 No. of bouts of vomiting    
 21 (53.9) 31 (79.5) 0.0035 
 1–4 8 (20.5) 6 (15.4)  
 5–9 6 (15.4) 2 (5.1)  
 10–25 4 (10.3) 0 (0)  
    Differences 
Mean  3.33 0.59 –2.74 
Median (range)  0 (0–25) 0 (0–7) 0 (–25, 7) 

0, no nausea; 3, severe nausea.

Table 2.

Impact of acupuncture on severity of nausea and number of bouts of vomiting in rheumatic patients on chemotherapy (n = 39) compared on two occasions close in time

Time after cyclophosphamide infusion Nausea (0–3) No acupuncture No. (%) Acupuncture No. (%) Comparison: no acupuncture/ acupuncture (P value) 
After 24 h 4 (10.3) 9 (23.1) 0.001 
 7 (18.0) 17 (43.6)  
 8 (20.5) 7 (18.0)  
 20 (51.3) 6 (15.4)  
After 48 h 6 (15.4) 17 (43.6) 0.0003 
 9 (23.1) 11 (28.2)  
 8 (20.5) 5 (12.8)  
 16 (41.0) 6 (15.4)  
After 72 h 12 (30.8) 21 (53.9) 0.0254 
 11 (28.2) 8 (20.5)  
 8 (20.5) 7 (18.0)  
 8 (20.5) 3 (7.7)  
 No. of bouts of vomiting    
 19 (48.7) 27 (69.2) 0.0007 
 1–4 9 (23.1) 9 (23.1)  
 5–9 6 (15.4) 3 (7.7)  
 10–25 5 (12.8) 0 (0)  
    Differences 
Mean  3.85 0.95 –2.90 
Median (range)  0 (0–20) 0 (0–7) 0 (–20, 6) 
Time after cyclophosphamide infusion Nausea (0–3) No acupuncture No. (%) Acupuncture No. (%) Comparison: no acupuncture/ acupuncture (P value) 
After 24 h 4 (10.3) 9 (23.1) 0.001 
 7 (18.0) 17 (43.6)  
 8 (20.5) 7 (18.0)  
 20 (51.3) 6 (15.4)  
After 48 h 6 (15.4) 17 (43.6) 0.0003 
 9 (23.1) 11 (28.2)  
 8 (20.5) 5 (12.8)  
 16 (41.0) 6 (15.4)  
After 72 h 12 (30.8) 21 (53.9) 0.0254 
 11 (28.2) 8 (20.5)  
 8 (20.5) 7 (18.0)  
 8 (20.5) 3 (7.7)  
 No. of bouts of vomiting    
 19 (48.7) 27 (69.2) 0.0007 
 1–4 9 (23.1) 9 (23.1)  
 5–9 6 (15.4) 3 (7.7)  
 10–25 5 (12.8) 0 (0)  
    Differences 
Mean  3.85 0.95 –2.90 
Median (range)  0 (0–20) 0 (0–7) 0 (–20, 6) 

0, no nausea; 3, severe nausea.

Eighteen patients had less than 5 acupuncture treatments, fourteen patients had 6–10, two patients had 12, two had 16 and three were treated 21–24 times. The median number of acupuncture sessions was 7 (range 2–24). The total number of acupuncture treatments was 294 for the 39 patients.

The effects of acupuncture on the severity of nausea and number of bouts of vomiting in patients treated with chemotherapy prior to acupuncture and at the first session of acupuncture are presented in Table 1 (described in the Methods section as analysis 1 comparing data from phase 1 and phase 2). At the start of chemotherapy and after 4 and 8 h there were no significant differences between treatment modalities, as most patients did not feel nausea at all after that short observation time. However, significant decreases in the severity of nausea with acupuncture were found after 24 and 48 h (P < 0.0001) and after 72 h (P < 0.0106). The mean number of bouts of vomiting was 3.3 without acupuncture compared with 0.6 when the patients were treated with acupuncture (P < 0.0035) (Table 1).

After receiving chemotherapy and acupuncture a number of times, 1–3 sessions of chemotherapy without acupuncture were measured again, and Table 2 compares the treatment modalities on two occasions close in time (in the Methods section described as analysis 2 comparing data from phase 3 and phase 4). There was a significant difference in the severity of nausea in the patients treated with acupuncture after 24 h (P < 0.0001), after 48 h (P < 0.0003) and after 72 h (P < 0.0254). The number of bouts of vomiting was significantly reduced when the patients were treated with acupuncture (P < 0.0007) (Table 2).

Other comparisons—not shown in the tables—were also made. First, between chemotherapy without acupuncture treatment and the last session of acupuncture (described in the Methods section as analysis 3, comparing data from phase 1 and phase 6). No significant differences were found in the initial period after acupuncture though differences in the severity of nausea were found after 48 h (P < 0.0151) and 72 h (P < 0.0080). There were no significant differences in the number of bouts of vomiting.

Finally, comparisons were made to evaluate if there was a cumulative effect of acupuncture on the degree of nausea and number of bouts of vomiting between the first and last sessions of acupuncture (described in the Methods section as analysis 4, comparing data from phase 2 and phase 6). Evidence of such an effect was observed. Significant differences were found in the severity of nausea after 48 h (P < 0.0059) and in the number of bouts of vomiting (P < 0.0005), but not in the rest of the observations.

As a whole, the patients kept their pattern of reaction to acupuncture and we assume that each acupuncture treatment had a similar effect on nausea.

Discussion

Compared with an efficient pharmacological anti-emetic treatment (ondansetron), it seems that acupuncture combined with ondansetron significantly decreased both the severity and duration of nausea, as well as the number of bouts of vomiting following intravenous cyclophosphamide therapy.

The details of the underlying mechanisms of acupuncture on nausea and vomiting are largely unknown. Acupuncture may affect the sympathetic system via mechanisms at the hypothalamic and brainstem levels. Indeed, the hypothalamic beta-endorphinergic system exerts inhibitory effects on the vasomotor centre. There is evidence that hypothalamic nuclei have a central role in the mediating effects of acupuncture and that afferent input of somatic nerve fibres has a significant effect on autonomic functions [1].

Why there is a potentiating anti-emetic effect of the combination of acupuncture and anti-emetic medication cannot be answered at present. It is apparent that the usual anti-emetic medication is not effective enough for many patients. Some of our patients (not included in this study) have tried acupuncture without ondansetron on some occasions, but found acupuncture alone to be unsatisfactory and therefore resumed the combined treatment with ondansetron and acupuncture.

There are some limitations in our study that deserve comments. Several previous acupuncture studies have been criticized for lacking adequate control groups. Although our study used the patients as their own controls, we had no placebo group. One reason for this is that placebo needles were not available when this study was initiated. On the other hand, it may be hard to ‘deceive’ patients using the currently available sham acupuncture methods.

Differences in the number of acupuncture treatments that patients underwent in this study depend to a certain extent on when the patients entered into the study. Some of the patients included here are still undergoing chemotherapy and data are still being collected from them.

The inclusion criterion was a prior treatment with cyclophosphamide followed by experience of nausea despite simultaneous treatment with ondansetron. As a good many patients on the ward did not experience nausea at all or did not consider it to be troublesome, they were thus not included in the study. The 39 persons who were both included and completed the study are in our opinion a group of patients with a generally more severe nausea problem.

Another limitation of the study concerns the response scale used to assess the severity of nausea. A ceiling effect may have resulted from setting the upper endpoint to 3, since judging from comments in the protocols the patients would have marked a higher score if such had been available. This may explain why some patients marked ‘3’ for nausea but still thought they were better off with acupuncture than without it. Furthermore, the follow-up period perhaps should have been extended to 5 or 7 days.

We conclude that acupuncture combined with ondansetron reduces nausea and vomiting compared with ondansetron alone and may thus be a treatment of benefit to patients with rheumatic diseases on chemotherapy. Based on the results from our study, we recommend acupuncture as a treatment to supplement anti-emetic drugs. As the method is reasonably easy to perform and carries minimal risk, its clinical use could be extended in order to make chemotherapy more endurable for patients. However, successful implementation of this treatment requires well-organized cooperation and planning among the staff. In our ward we have developed a carefully planned schedule to accommodate this treatment. The treatment days are concentrated to 2 days a week. Blood tests are taken the day before the cyclophosphamide infusion, which makes it possible to start all infusions at the same time on each occasion. This enables us to administer acupuncture routinely despite the hectic working situation on our ward.

Supported by grants from the F.R.F.-Foundation, Sweden, the Swedish Rheumatism Association, Legitimerade Sjukgymnasters Riksförbunds Minnesfond and the Rune and Ulla Amlöv Foundation.

Conflict of interest

The authors have declared no conflicts of interest.

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Author notes

Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Göteborg and 1Institute of Occupational Therapy and Physiotherapy, Göteborg University, Göteborg, Sweden.

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